TARGET ONCOGENIC RECEPTORS IN TUMOURS, FROM ITS INITIAL CLINICAL BREAKTHROUGHS TO CURRENT CLINICAL STANDARD THERAPY

 George Zhuimage 

Khalifa University, United Arab Emirates. The Civil Affairs Bureau,Wugang, Hunan, China.

ABSTRACT

Epidermal growth factor (EGF) which originally isolated from mouse submaxillary gland had its key role in the proliferation, differentiation, and survival of neural and glial precursor cells. The physiological effects of EGF are through an EGF receptor (EGFR) with tyrosine kinase activity. The traditionally accepted view is that normal EGFR is no tumorigenic, whereas mutated EGFR such as an oncogenic receptor EGFRvIII is oncogenic. Recently, EGF was found to be beneficial for wound healing, burn and diabetic foot ulcer, and show an attractive perspective in future. Moreover, cosmetic containing EGF play the control role of the amount of erythema and sebum in the skin, anti-aging and whitening, and improving the plasticity of skin. Based on these data, our team has successfully prepared a series of 350 bottles of Shampoo liquid containing EGF and 26 bottles of recombinant human EGF spray, and 4 bottles of EGF-Silvadence ointment. The initial results showed that prepared rhEGF is safe and available in clinical use. On the other hand, progress on the interaction of EGF coupled with its altered oncogenic receptor signaling via its downstream molecules such as Ras/Raf/MAPK and/or PI3k/akt in growth and progression of some cancers such as brain glioblastoma, lung cancers, breast, pancreas and A431 human epidermoid carcinoma cells. In addition to a series of target drugs gefitinib, erlotinib, osimertinib and the CIMAvax-EGF vaccine, an antioncogenic receptor antibody based fusion protein [eg. Cetuximab-based IL-10 fusion protein, CmAb-(IL10)2] could improve cancer immunotherapy.

Keywords: EGF, EGFR, oncogenic receptor EGFR VIII, Target therapy.

 

INTRODUCTION

 

The biological activity of EGF and its normal EGF receptor (EGFR)

In earler 1989-91, the discovery of oncogenic receptor and its earliest described Ras/Raf/MAPK pathway in cell signaling in concise figure from George Zhu’s research work that oncogenic pml/RARa fusion in a specific APL and androgen/androgen receptor oncogenic signaling in hormonal tumorigenesis, this is a new area and its novel etiology of hormonally driven cancers even growth factors involved in this event (process)1-5. In the pharmacology textbook, the most notably, Dopamine which was synthesized in 1910, an old clinical drug, was mediated through its D2 dopamine receptor (DRD2) in inducing role of VEGFR2/KDR/FIk-1 endocytosis and angiogenesis. ONC201 is the first clinical bitopic antagonist of classical DRD2, an oncogenic receptor in brain and neuroendocrine tumors6. DRD2 activation has been found to promote self-renewal in breast cancer cells by activating STAT3 and IL-67. Here, DRD2 is not an oncogene, and it represents the mechanism of dopamine drug action. Now many studies in this field are dedicated on their clinical targeting therapy. There are presently thousands of publications and over 200 ~ 400 global journals which are focused on this area targeting oncogenic receptor or oncogenic receptor (tyrosine) kinase in tumours. p38 MAPK family are found many subtypes, which are included p38α (MAPK14), p38β (MAPK11), p38γ (MAPK12), and p38δ (MAPK13). The traditionally accepted view is that normal epidermal growth factor receptor (EGFR) is no tumorigenic8, this is importance in distinguishing normal epidermal growth factor receptor from oncogenic receptor EGFR. Epidermal growth factor (EGF) contains 53 amino acids residues with intra-molecular disulfide bonds that are required for its biological activity. Such as stimulating or inhibiting proliferation, differentiation and angiogenesis in various of cells, e.g. fibroblasts, keratocytes, myofibroblasts, epidermal cells, corneal epithelial cells9-11. EGF also play a role in every tissue in the body during development and in the adult, the exact nature of this role is not clear. EGF interacts with its specific EGF receptor which located at the cell surface12.

The cell surface EGFR, i.e.,170,000 dalton, tyrosine kinase transmembrane receptor along with a member of the human EGFR (HER) family which constitutes four transmembrane receptors that interact with each other, i.e., EGFR/HER1, HER2/neu, HER3, and HER4. EGFR consist of a 621- amino acids extracelluar EGF binding, a single transmembrane region of 23 amino acids and a 542-amino acids cytoplasmic domain13. In epidermal keratinocytes, the binding numbers of normal EGFR was 1.5x105 binding sites/cell14. EGF bind to EGFR complex induced EGFR autophosphory-lation and the activation of two of the major EGFR downstream- signaling transduction pathways, extracellular signal-regulated kinase (Ras/Raf/ MAPK (MEK)/ERK)5,15-31 (Figure 1) and phospho-lipase C(PLC)-r, which regulate transcription factors leading to proliferation of skin and other epithelial tissue. EGFR regulates important process including cell survival, cell cycle progression, tumor development, invasion and angionesis, and metastasis etc. biological action.

EGF accelerate wound healing

Advances in the knowledge of pathway, it has been suggested that EGF could be beneficial for burn, wound healing, diabetic foot ulcer, and provide an attractive perspective11,32-35. In mice wound experiments (Table 1)11, it has been observed that a dose-dependent stimulatory effect of EGF on wound healing was consistent with increased hEGF concentration. Treatment with rhEGF significantly decreased the length of time to over 59% healing by approximately 4-5 days, and that to 90% healing by 3 days, respectively. The initial results showed that prepared rhEGF may assist in clinical wound healing time, and is safe and available. Moreover, cosmetic containing EGF could be effective to show whitening, to remove wrinkle, and anti-aging, and control of erythem amount and sebum amount on the human skin care. In this regard, George Zhu and Zhi QW have successfully prepared a series of 350 bottles of Shampo liquid (New Washing) and 26 bottles of recombinant human EGF spray, and 4 bottles of EGF-Silvadence ointment into market11. The responder rate with perfect satisfied and satisfied was over 95 per cent. For instance the detail investigation as to me, aged 60 years. In my own hair for many years, after using Lux soap, there was the phenomenon of dry hair on the forehead. A small white patch on the head. When changing to this Shampoo, no more dry and dandruff on the forehead was seen. This fact indicate that the head skin showed a satisfied effects of moisture retention. The author in this paper has used this hair shampoo for 5 years. The second case, aged 73 years, the wound did not heal for over a year after minor surgery. He wipe the wound of flowing water with tissue every day. After using EGF-Silvadence ointment, surprisingly, there was no fluid flowing out of the wound for 24 hrs. Later, the wound was relapsed once again. After using Shampoo containing EGF for 2 years, the recurred wound achieved cure once again. The results implicate EGF in the possible role of wound healing. Another a 42- year-old police officer here has multiple black naevus cutaneus on his right face. After a period of 2 years of Shampoo, the black naevus had obviously fade and/or even disappearance of 2 tiny naevus around right eye, indicating the role of rhEGF in whitening on the human skin care. Now, epidermal growth factor (EGF) was included as an additive ingredient in cosmetics, including hair Shampoo. Actually, EGF is the secreted protein by skin epithelial cells in epidermis. The detail preparation of rhEGF agents has been described in other elsewhere11.

Oncogenic receptor EGFRvIII in malignant cells and its targeting immunotherapy

On the other hand, malignat cells share oncogenic receptors11,36-58. The most common primary brain tumors are malignant gliomas including glioblastomas (GBM) and anaplastic astrocytomas. Aggressive human glioma often express a truncated and oncogenic form of the epidermal growth factor receptor, known as oncogenic receptor EGFRvIII5,11,36-40,42-58. 

EGFRvIII is the deletion of cDNA nucleotids 275-1075 (exons 2-7) within the extracellular domain of the EGFR, which encode amino acids 6-276 in the EGFR protein. This deletion of 801 bp in the EGFR results in a in-frame trunction of the normal EGFR protein, a 145-kda receptor8. This EGFRvIII occurs in up to 30% of high-grade gliomas especially glioblastoma multiforme  (GBM). Amplification and high expression (as high as 6- to 60-fold) of EGFR in GBM may drive tumor growth and proliferation to a significant degree59. In the 2021 WHO classification of central nervous system tumors, EGFR amplification, but not EGFRvIII expression, is a diagnostic criterion for GBM, IDH- wild type, when histopathological criteria do not allow for definitive diagnosis. The oncogenic receptor EGFRvIII and platelet derived growth factor receptor (PDGFR) induced Src-mediated tyrosine phosphor-rylation of DOCK1 (dedicator of cytokinesis) to activate Rac1 and promote cell migration and invasion, suggesting a potential targeted therapeutic window. Recent genetic studies in medulloblastoma (MB) metastasis also revealed that G protein-coupled receptor kinases (GRKs) can regulate EGFR and PDGFR activity at the mRNA and protein level by altered oncogenic receptor signaling, and involved in cancer metastasis through their regulation of G-protein coupled receptors (GPCRs) in growth factor (GF)-mediated cell migration60. 

The prognosis for malignant gliomas remains poor. Begin in 2004, concomitant temozolomide (TMZ) with fractionated brain irradiation (gamma knife radiosurgery, or whole brain radiotherapy WBRT) were known the standard of care at most neurooncology centres in Europe and the USA61. In 2010, McGirt62 treated with combined modalities Carmustine (Gliadel) plus concomitant TMZ in 37 GBM patients, and the median survival (OS) was 20.7 months, with a 36% of 2-year survival rate. Targeted toxins (immunotoxins) represent a new class of anticancer agents with high specificity for tumor cells selectively overexpressing surface proteins such as EGFR63. At present, various single agent targeted therapies, such as EGFR inhibitor gefitinib and imatinib have failed to successfully improve survival benefits. In recurrent GBM with gefitinib treatment, the 6-month progression-free survival (PFS-6) was 13-14.3% and a median overall survival (OS) time from initial treatment was 24.6-39.4 weeks. Erlotinib treatment was equally as effective as the standard regimen (median OS 58 weeks, median PFS 6.9 months, 11.3% CR (n=7) and 27.4% (n=17) partial response (Table 2)61,64. In the EORT randomized phase II trial, 54 recurrent GBM treated with erlotinib and 56 with TMZ or BCNU (bis-chloethylnitrosourea), showing that PFS at 6 months was 12% for erlotinib and 24% for the control, and an similar OS in both arm65. In overall, the median OS in gliomas varies in different trials, but is generally to be 18-20 months for anaplastic astrocytomas and 8-14 months for GBM 63. Otherwise, Vredenburgh et al.,66 conducted a phase II trial of bevacizumab (10 mg/kg) and irinotecan in 23 patients with recurrent grade III-IV glioma. The median PFS was 23 weeks for all patients. The PFS-6 and the 6-month OS were 38% and 72%, respectively. The drug action is through binding to VEGFR-2. The combination of anti-human VEGF bevacizumab and irinotecan is therefore an active regimen and benefits for recurrent III-IV glioma.

Many studies were in recent focused on brain and leptomeningeal metastases in patients with non- small cell lung cancer (NSCLC), and breast cancer brain metastases (BCBM).The leptomeningeal metastases (LM) from lung cancer account for 5-29% of LM from solid tumors. The patients with LM from lung cancer had a median survival of only 1-1.8 months without treatment67 and 2 to 5 months with whole brain radiation therapy68, and and median survivals of 4 to 6.5 months with chemotherapy69. In clinical trials, when compared with chemotherapy, the first-line treatment with reversible EGFR-TKIs, such as gefitinib or erlotinib may improve progression-free survival (PFS).  Gefitinib or erlotinib for NSCLC harboring EGFR mutation had unexpected activity against brain and leptomeningeal metastases. The ability of high dose (500-1250 mg/day) gefitinib or erlotinib to cross the blood brain barrier render their use of multiple intracranial lesions, which was in particular reported. The median PFS and median OS on first-line EGFR- TKIs were 19.0-12.68 months and 27.69-28.0 months, respectively. In a cohort of 23 patients with lung adenocarcinoma and asymptomatic brain metastasis70, treatment concluded oral gefitinib 250 mg or erlotinib 150 mg once daily. 65.2% (13/23) of available patients obtained partial response (PR), 13% (3/23) had stable disease (SD), and a disease control rate of 79.3%. Median PFS and OS were 6.4 months and 18.6 months, respectively. First-line afatinib is also effective in NSCLC with CNS metastases. Total 42% (13/31) of the evaluable patients experienced a PR on afatinib, 39% (12/31) had SD. The overall rate of cerebral response to treatment with afatinib was 35%. The overall survival (OS) was 9.8 months71.

Among those isolated case reports, there were at least more 20 cases to bring about our clinical practice efficacy. Sakai et al.,72 presented a 40-year-old Japanse case of carcinomatous meningitis from NSCLC. The patient obtained an over 4 months of complete response after the initiation of a dose of 250mg/day gefitinib, and was able to work. Jackman et al.,73 presented a 53-year-old white man with stage IV adenocarcinoma (2 cm tumor) of the lung harboring an exon 19 deletion (2239-2247del TTAAGAGAA) of the EGFR. The patient achieved a partial response to treatment with carboplatin, paclitaxel and 250 mg/day gefitinib. After September 2004, because of his adenocarcinoma cells in the CSF, gefitinib dose was escalated from 500 mg/day to 750 mg/day and then to 1000 mg/day over a period of 10 weeks. At the highest gefitinib CSF concentration (42 nmol/l), the cytologic CSF showed no evidence of malignant cells. As the marked improvemen of his carcinomatous meningitis and related symptoms, he was able to return to work. He obtained a near one year of overall survival at initiation of EGFR-TKI therapy. Muller74 presented a six weeks of CR in a 43-year-old German woman with NSCLC with cerebral metastases following initiation of a dose of 250mg/day gefitinib. Hata et al.,75 reported a 56-year-old woman with metastatic NSCLC harboring an EGFR mutation (exon 18 G719N) on analysis of the malignant effusion. Gefitinib was then given following chest tube drainage, and a partial response was achieved for approximately 1 year. After disease progression on gefitinib, she carried out WBRT due to her brain lesions, subsequently, changed to erlotinib in 2009, and with a disease stable for 4 months. Moreover, a high dose of 300 mg/day erlotinib was given due to her deteriorated brain lesions.

Two weeks later, both her clinical symptoms and findings of MRI imaging improved, and in further remained stable for 6 months. Yuan reported a 52- year- old Chinese man with stage IIIA lung adenocarcinoma harboring an exon 19 deletion (L747- S752del5) and a point mutation (K754I) in exon19 of EGFR who developed multiple brain metastases one year after operation76. After an oral 250 mg/day gefitinib with concomitant WBRT as first-line therapy, the patient achieved a 50 months of PFS. Subsequently, a dosage of 500 mg/day gefitinib combined with pemetrexed were used as the second-line treatment due to new brain lesions and leptomeningeal metastases. The patient obtained a total overall survival of 59 months.

Another attention was focused on the efficacy of erlotinib for the treatment of brain and leptomeningeal metastases instead of high dose gefitinib failure. Katayama et al.,77 used erlotinib administration in treatment of 7 lung adenocarcinoma with EGFR mutation who had shown an initial good response to gefitinib (2CR, 2PR, 2SD; initial PFS 310 days, range: 113-1211 days). 3 patients obtained PR, 3 had SD. The overall survival (OS) from the initiation of erlotinib ranged from 15 to 530 days. The Spanish Lung Cancer Group78 monitored a group of chemotherapy- naive, EGFR-mutated NSCLC patients with intracranial lesions who were treated with erlotinib: 4 CR and 3 PR were reported. Lai and Boshoff79 presented a 55-year-old case of recurrent NSCLC harboring EGFR L858R mutation had complete remission in brain disease after using 150 mg/day erlotinib. Fekrazad et al.,80 reported a 60-year-old case of a non-smoking native American woman who had a complete resolution of brain metastases from a lung adenoarcinoma after 8 months of using oral 150 mg/day erlotinib. Clarke et al.,81 also successfully controlled LM from a 54-year- old woman with stage IV lung adenocarcinoma harboring EGFR mutation using intermittent high dose erlotinib (1000-1500 mg/week), with concurrent high CSF concentration. She survived 14 months following the diagnosis of CNS disease. Bendetti (2009)82 reported in Italy that 2 cases of NSCLC harboring EGFRexon19 deletion mutation had compete response following a dose of 150 mg/day erlotinib. A 44-year-old case of multiple intracranial metastases (MIMs) from lung adenocarcinoma with L747-P753 deletion of EGFR exon19. He had complete remission of MIMs after 8 months of 150 mg/day erlotinib treatment. Another a 48-year-old woman with lung cancer had the diasappearance of MIMs completely after 4 months of 150 mg/day erlotinib. Molecular analysis of a lung neoplasm found an EGFRexon19 deletion (K745- E749del). The disease remained stable after 24 months of erlotinib treatment. These case reports are encouraging.

EGFR mutation is an oncogenic driver in advanced lung cancer that is clinically responsive to EGFR-TKIs

The major of lung cancer is diagnosed at an advanced stage with 5-year survival with conventional chemotherapy regimens of about 5%. A rising incidence of NSCLC subtype harbors a particular activating EGFR mutation. EGFR mutation (Exon19 deletion, Leu858Arg, Exon20 insertion, EGFR-KDD, EGFR–RAD51 fusion) act as an oncogenic driver of NSCLC in non-smokers and light-smokers83-96. Targeting for EGFR specific tyrosine kinase inhibitor (EGFR-TKI) therapy was considered, since targeted therapies results in superior outcomes compared with chemotherapy.

To date, four major mutation of EGFR in human lung adenocarcinoma has been described97: substitutions for L858 in exon 21 and for G719 in exon 18, in-frame deletions within exon 19, and in-frame insertions within exon 20. In the area of advanced NSCLCs target therapy, two pivotal studies in earlier 200497 showed that in lung cancer activating EGFR mutations strongly correlates with its clinical response to gefitinib. Since then, three generations EGFR-TKIs entered as the first line treatment in NSCLC patients with mutated EGFR. Gefitinib (Iressa), the first EGFR-TK inhibitor (gefitinib in 2002, erlotinib in 2003) was through competitively binding to the ATP binding site at EGFR intracellular domain, which inhibits the phosphorylation of EGFR tyrosine kinase, and blocks downstream signaling and EGF-dependent prolife-ration. Gefitinib and erlotinib have a higher binding affinity for EGFR exon 19 deletion and exon 21 substitution mutations than for wild-type EGFR. Drugs half-life of gefitinib was 48 hours and erlotinib 36.0 hours respectively. Erlotinib is about 60% absorbed after oral administration and its bioavailability is significantly increased by food to almost 100%. Second generation EGFR TKI, afatinib is an orally available, irreversible HER family blocker. As a third generation EGFR TKI, Osimertinib binds to certain mutant forms of EGFR (T790M, L858R and exon 19 deletion) that predominate in NSCLC tumours who have progressed on or after first-line EGFR-TKI therapy98,99. Osimertinib is about 200-fold more potent against the T790M mutation than its wild-type counterpart, which irreversibly binds to the cysteine in a covalent manner at C797 in EGFR kinase domain. Therefore, approximately 10% of patients with NSCLC harboring activating EGFR mutation are beneficial to dramatic response to EGFR-TKIs.

Emerging clinical trials in the comparison of three generation EGFR-TKIs clearly showed that there were significantly longer median progression free survival (PFS) and median overall survival (OS) in EGFR-TKIs compared with standard chemotherapy. Notably, Osimertinib was indicated in NSCLC patients with CNS metastases. In these personalized management for an individual with lung cancer, Balk et al.,100 in 2015 presented a case of metastatic lung cancer harboring TKD-EGFR mutation who had a greater than 10 years response to EGFR-TKI therapy (gefitinib in 2003 to 2009, and then erlotinib in late 2009 until late 2014). The patient with overall survival (OS) was approximately 20 years later. At the same year, Gallant et al.,86  also identified a 33-yer-old metastatic lung adenocarcinoma harboring oncogenic EGFR kinase domain duplication (EGFR- KDD) that is clinically responsive to afatinib (-50% tumor shrinkage) for 7 cycles of therapy. Hirokawa et al.,87 also presented a 45-year-old Japanese woman with NSCLC positive for EGFR- KDD who developed carcinomatous meningitis and showed a marked response to erlotinib and osimertinib. She achieved a complete response of CNS metastases, and Osimertinib was effective for 14.5 months. Her overall survival was 44 months from the start of the carboplatin-pemetrexed chemotherapy and first-line EGFR-TKI therapy. Konduri and colleagues88 reported five patients with metastatic lung cancer whose tumors harbored EGFR fusion, most commonly RAD5, are recurrent in lung cancer. Four of whom were treated with EGFR-TKI erlotinib with documented antitumor response for 5, 6, 8, and 20 months respectively. More data, Zochbauer-Muller and Mullauer et al.,89 described a patient with NSCLC, a multiple adenocarcinoma harboring an EGFR exon 20 insertion mutation who achieved durable stable disease with afatinib (initial 40 mg/day in July 2015, and then dose reductions to 20 mg/day) and remains on treatment after 4.5 years. Faehling et al.,90 reported a longest survivor (99.2 months) who was a male patient with stage IV disease at diagnosis and a complex EGFR exon 18 mutation (E709A and G719S). In our 2 patients with advanced lung cancers, we used oral gefitinib (250 mg/day) in keeping stable disease for 8+ months in a 64-year-old female patient with multiple metastatic adenocarcinoma of the lung, and the overall survival(OS) was over 18 months101. Moreover, in my follow up, a 72-year-old woman with advanced lung cancer (a half the size of an egg). After using oral gefitinib in other hospital, she achieved a 4 years survivor. In a cohort of 114 advanced T790M positive NSCLC with brain metastases, progression free survival in the osimertinib group was 8.5 months, compared to the platinum-based therapy group at 4.2 months102. Therefore, three generations EGFR-TKIs can be used as first-line therapy and/or second or third line therapy for stage IIIB/IV NSCLC with oncogenic EGFR mutation that are not suitable for chemotherapy. It is noteworthy that despite higher tumor response rates with first line EGFR- TKIs, disease progresses in a majority of lung cancer after 9 to 13 months of treatment. Acquired resistance to all three generation EGFR-TKIs, especially osimertinib resistance raise new challenges to the long-term effective strategies of those NSCLC patients. Table 3 showed the characteristics of patients to objective detail response to EGFR- TKIs treatment in different practical trials.     In Cuba, the CIMAvax-EGF vaccine trial is another promising strategy for stage IIIB or IV NSCLC with one line of chemotherapy previously. In phase II clinical trial121, patients received at least four doses of CIMAvax-EGF had a significant effects on survival time. The mean survival was 19.47 months in 20 patients with good antibody responders (GAR),4.97 months in PARs (poor antibody responders) (n=18), and 8.52 months in 37 controls. More data, anti-EGF antibody titers in a phase III trial in 112 patients with advanced III/IV NSCLC122 was evaluated (89 GAR and 24 patients with super-good responders)122. Mean survival time (MST) was 10.83 months in the vaccine arm versus 8.86 months in the controls. Using at least one dose of CIMAvax EGF vaccine123, the median overall survival (mOS) was 7.0 months, and mOS 9.98 months in a total of 927 patients with at least 4 doses of CIMAvaxEGF compared with only 3.97 months in chemotherapy. Total 44.4% and 23.3% of the patients who completed the induction phase of treatment was still alive at 1 and 2 years, respectively. Two patients with GAR criterion had significant benefits with the longest 7 and 8 years survivor. In recent, from doctor a 75-year-old chinese woman with stage IV NSCLC harboring EGFR mutation had 6 years long survivor. The vaccine could induce antibodies against self EGFs that block EGF-EGFR interaction. Thus, CIMAvax-EGF is a very safe drug that could be a feasible intervention for long-term control of those NSCLC patients with tumors depending on the EGF, capable of produce a rapid and durable response.

 

CONCLUSIONS

 

In the past thirty years ago, Zhu is the earliest to introduce that target therapy is mainly toward oncogenic receptors (also molecular “missile therapy”) 1,101. In 1994, edrecolomab (mAb17 -1A) was the first to show its clinical efficacy in increasing disease-free survival in cancer, 3 of 20 patients with metastatic resected colorectal adenocarcinoma had no detectable disease for 10, 13 and 22 months5,124,125. Subsequently, more effective anti-EpCAM antibodies engineering (adecatumumab, catumaxomab, NEA125, ING101,and other EpCAM-specific immunotoxin)144,145 are used in clinical trials. The European Medicines Agency in 2009 approved catumaxomab, which binds to oncogenic receptor EpCAM5,142,143 and enhances the immunological response against EpCAM- positive cells in malignant ascites.  

In 1998, a targeting drug trastuzumab approved by the US FDA was demonstrated to be enough to slow tumor growth and progression126-139. In HER2+ metastatic breast cancer, ado-trastuzumab emtansine and trastuzumab enables lysosomal degradation of its cognate oncogenic receptor HER2 or release of prodrugs via antibody- dependent cellular cytotoxicity (ADCC) 126-128,150. This burgeoning class of targeted chemotherapies in recent called antibody drug conjugates. In 2001, another novel agent called imatinib proved to be effective in chronic myeloid leukemia (CML) and received full approved by the US FDA in 2003140,141. As an orally targeting bcr-abl oncogene kinase, Gleevec (imatinib) has been used in breakthrough in treatment of chronic myeloid leukemia. Imatinib is also indicated for GIST patients with oncogenic receptor tyrosine kinase (RTKs) or also oncogenic receptor PDGFR mutants and KIT /or HES, and myeloproliferative neoplasm with oncogenic PDGFR fusion146-148, and inhibits activation of Ras/raf/MAPK or PI3k/Akt pathway. BMS-354825149 competes with ATP for the ATP-binding site in the kinase domain of selected and related oncogenic receptor and non- receptor protein tyrosine kinases (PTKs), including BCR-ABL, c-KIT, and PDGF receptors. During the follow up of May 2023 in my group, a 63-year-old man was diagnosed as his primary hepatocellular carcinoma after biopsy of liver tumor tissue (2.0x2.4cm tumor in the right anterior lob of his liver in August 23, 2012) on April 26, 2013. He had a past history of viral hepatitis B (HBV) infection. The patient was therefore performed his hepatectomy in other hospital, with then the combination of oncogenic receptor tyrosine kinase inhibitor Sorafenib Tosylate Tablets (initial dosage 2#/day (2 x 0.2g) x 5 months, and then 1#/day intermittent until to 1.5 years). He was a long survivor now. To date, 34 more drugs have been introduced to clinical trials of various cancer. Down regulating oncogenic receptors, currently the first or third-line setting of targeting therapy might be useful in those hematological malignancies, metastatic and advanced cancers151-161.

PI turnover: Phospholipase Cr (PLCr) is activated by receptor tyrosine kinase (RTK) through the binding of its SH2 (syc-homology 2) domains to phosphotyrosine (PY) sites of the receptor. Also, the SH2 domain binds specifically to sequences containing a phosphorylated tyrosine motif. After activation, PLCr hydrolyses its substrate ptdins (4, 5) p2 (PIP2) and forms two second messengers, diacyclglycerol (DAG) and Ins (1, 4, 5) p3 (IP3). IP3 bind its receptor that stimulates the release of Ca2+ from intracellular stores. DAG activate members of the protein kinase C (PKC) family. Ca2+ then binds to calmodulin, which subsequently activates a family of calmodulin dependent protein kinases (Camks). The second messengers generated by PIP2 hydrolysis stimulate a variety of intracellular processes such as cell motility, proliferation, and angiogenesis 15,16. 

PI3-K/Akt pathway: The class phosphatidylinositol 3- kinase (PI3-k) is activated by the majority of oncogenic RTKs. Like other SH2 domain-containing proteins, PI3 kinase forms a complex with PY sites on activated receptor. The main function of PI3K activation is the generation of PIP3 (ptdins (3) p), which function as a second messenger to activate downstream tyrosine kinase Btk and Itk, the ser/thr kinase PDK1 (phosphoinositide- dependent protein kinase 1) and Akt (Protein Kinase B, PKB). The major biological functions of Akt activation is involved in cell survival, anti- apoptosis and proliferation and cell growth. Akt is also known to be implicated in several cancers, particularly breast cancer. Proteins encoded by the Syc and ros oncogenes may functions as inositol lipid kinases in convert phosphatidylinositol (PI) into PtdIns (4,5) P2 process15,16.

Ras/Raf/MAPK: In Ras/MAPK signal pathway, each of three closely related mammalian ras oncogene (H-ras, K-ras and N-ras) encode a 21-KD protein (p21) of 188 or 189 amino acids which are located at the inner surface of the cell membrane. Ras protein are guanine nucleotide binding proteins with a low intrinsic GTPase activity that can switch from an inactive GDP-bound form to an active GTP-bound. The 120kd cytoplasmic protein (referred as GAP, GTPase activating protein) interacts with normal Ras GTP at p21 effector site and stimulates its intrinsic GTPase activity dramatically to down-regulate Ras GTP. Ras p21 residues thus appear to be required for GAP effector binding. Also, GAP interaction may be essential for Ras p21 biological activity. P21 mutated at codons 12, 13 and 61 abolish the intrinsic GTPase activity, the resulting oncogenic protein can still bound GTP. Thus, in the signal transducing G proteins, they are biologically active when in the guanosine triphosphate (GTP)-bound form and inactive when bound to guanosine diphosphate (GDP)17-19. GAP is phosphorylated on tyrosine in response to PDGF or EGF. After stimulation of cells (in 3T3 cells and in CHO cells) with PDGF, GAP physically associated with PDGF receptor and with PI-3 kinase (3’ phosphatidylinositol kinase, 85kd), c-raf (a cytoplasmic serine/threonine kinase, 74kd) and PLC-r (140kd). This association occurs via a SH2 domain of the receptor. A 83 amino acids deletion in the mutant PDGF receptor (“kinase insert domain”) that blocks PDGF induced mitogenesis, also blocks binding of PI-3 kinase, but not PLC-r or c-raf. This deletion also blocks GAP binding, implying that GAP and PI-3 kinase are essential components of the mitogenic response. EGF also increases the binding of GTP to Ras p21, whereas GTP-binding protein may thus extend in controlling cyclic AMP production. Thus the association of p21 Ras GAP with ligand-activated PDGF receptor may directly link growth factors and Ras signaling transduction from the plasma membrane into the cell17-22,24.

Also, the adaptor protein growth factor receptor-bound protein 2 (Grb2) forms a complex with SOS (son of sevenless) protein by the Grb2 SH3 domain. Grb2 or Grb2/SOS complex is recruited to the membrane by the Grb2 SH2 domain binding to activated PDGFR bound SHP2, thereby allowing interaction with Ras and the exchange of GDP for GTP on Ras via GTPase hydrolysis. Whereas the interaction between Grb2 and activated PDGFR occurs through interaction with the SHP2 protein, Grb2 binds to oncogenic EGFR through Shc, another adaptor protein that forms a complex with many receptors via its phosphotyrosine binding domains (PTB)17-31. This Shc-Grb2/EGFR complex activate Ras. 

After activation, subsequently, Ras interacts with several proteins, namely Raf. Activated Raf stimulates mitogen- activated protein kinase (MAPK) kinase (MAPKK or MEK) by phosphorylating a ser residue in its activation loop. MAPKK then phosphorylates MAPK (ERK1/2) on T or Y residues at the active loop leading to its activation. Activated MAPK phosphorylates a variety of cytoplasmic substrates, as well as transcription factors and other kinases, when translocated into nucleus, and thus contribute to the regulation of different cellular processes such as cell survival, apoptosis, proliferation, differentiation, and immune responses. At present, Ras/MAPK/ERK、PI3-K/Akt pathway act as the major oncogenic signaling.

 

ACKNOWLEDGEMENTS 

 

Author is thankful for the Khalifa University, United Arab Emirates. The Civil Affairs Bureau, Wugang, Hunan, China to provide necessary facility for this work.

 

DATA AVAILABILITY

 

Data will be made available on request.

 

CONFLICT OF INTEREST

 

None to declare.

 

REFERENCES

 

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