Advances in molecular mechanisms and targeted therapy of gastric cancer associated withthe RTK/RAS signaling pathway_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

FAN Chuanlei ¹ , HE Yang ² ,  DA Mingxu ^1,3

1. The First Clinical Medical College, Lanzhou University, Lanzhou 730000, P. R. China;
2. The First Clinical Medical College, Gansu University of Traditional Chinese Medicine, Lanzhou 730000, P. R. China;
3. Department of Surgical Oncology, Gansu Provincial Hospital, Lanzhou 730000, P. R. China;

Corresponding author：

DA Mingxu, Email: hxdamingxu@hotmail.com

Keywords：

gastric cancer; RTK/RAS signaling pathway; molecular mechanism; targeted therapy

DOI：

10.7507/1007-9424.202306035

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To understand the molecular mechanisms and targeted therapy research progress of gastric cancer associated with the RTK/RAS signaling pathway, in order to provide reference for treatment of gastric cancer. Method The related literatures about the molecular mechanism and targeted therapy of RTK/RAS signaling pathway related gastric cancer at home and abroad in recent years were reviewed. Results Targeted therapy had been widely applied in the treatment of gastric cancer associated with the RTK/RAS signaling pathway, showing good efficacy and significantly prolonging patients’ survival time, further deepening the understanding of the molecular mechanisms of gastric cancer. Targeted therapies for gastric cancer associated with the RTK/RAS signaling pathway focused on human epidermal growth factor receptor 2 (HER-2), epidermal growth factor receptor, fibroblast growth factor receptor 2, cellular-mesenchymalepithelial transition factor and Kirsten ratsarcoma viral oncogene homolog associated targets. Currently, there were many drugs targeting HER-2 target, while research on other targets mostly remains in the clinical trial stage, and showing promising prospects. Conclusion Targeted therapy can benefit most patients with gastric cancer, but the drug resistance and multi-drug combination therapy are still difficult problems that we need to overcome in the future.

Citation： FAN Chuanlei, HE Yang, DA Mingxu. Advances in molecular mechanisms and targeted therapy of gastric cancer associated withthe RTK/RAS signaling pathway. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2023, 30(11): 1402-1408. doi: 10.7507/1007-9424.202306035 Copy

1.	Siegel RL, Miller KD, Fuchs HE, et al. Cancer Statistics, 2021. CA Cancer J Clin, 2021, 71(1): 7-33.
2.	Chen Y, Chen T, Fang JY. Burden of gastrointestinal cancers in China from 1990 to 2019 and projection through 2029. Cancer Lett, 2023, 560: 216127.
3.	Sun D, Li H, Cao M, et al. Cancer burden in China: trends, risk factors and prevention. Cancer Biol Med, 2020, 17(4): 879-895.
4.	Pihlak R, Fong C, Starling N. Targeted therapies and developing precision medicine in gastric cancer. Cancers (Basel), 2023, 15(12): 3248.
5.	Joshi SS, Badgwell BD. Current treatment and recent progress in gastric cancer. CA Cancer J Clin, 2021, 71(3): 264-279.
6.	Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature, 2014, 513(7517): 202-209.
7.	Deng N, Goh LK, Wang H, et al. A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut, 2012, 61(5): 673-684.
8.	Lv Q, Meng Z, Yu Y, et al. Molecular mechanisms and translational therapies for human epidermal receptor 2 positive breast cancer. Int J Mol Sci, 2016, 7(12): 2095.
9.	Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet, 2010, 376(9742): 687-697.
10.	Wagner AD, Grabsch HI, Mauer M, et al. EORTC-1203-GITCG— the “INNOVATION”-trial: effect of chemotherapy alone versus chemotherapy plus trastuzumab, versus chemotherapy plus trastuzumab plus pertuzumab, in the perioperative treatment of HER2 positive, gastric and gastroesophageal junction adenocarcinoma on pathologic response rate: a randomized phaseⅡ-intergroup trial of the EORTC-Gastrointestinal Tract Cancer Group, Korean Cancer Study Group and Dutch Upper GI-Cancer group. BMC Cancer, 2019, 19(1): 494.
11.	Gong J, Liu T, Fan Q, et al. Optimal regimen of trastuzumab in combination with oxaliplatin/ capecitabine in first-line treatment of HER2-positive advanced gastric cancer (CGOG1001): a multicenter, phaseⅡ trial. BMC Cancer, 2016, 16: 68.
12.	叶春, 祁兴顺, 李谦谦, 等. XELOX联合曲妥珠单抗在HER2阳性老年晚期胃癌转化治疗中的疗效观察. 中国普外基础与临床杂志, 2022, 29(12): 1623-1627.
13.	Kurokawa Y, Sugimoto N, Miwa H, et al. PhaseⅡstudy of trastuzumab in combination with S-1 plus cisplatin in HER2-positive gastric cancer (HERBIS-1). Br J Cancer, 2014, 110(5): 1163-1168.
14.	Kagawa S, Muraoka A, Kambara T, et al. A multi-institution phaseⅡstudy of docetaxel and S-1 in combination with trastuzumab for HER2-positive advanced gastric cancer (DASH study). Cancer Chemother Pharmacol, 2018, 81(2): 387-392.
15.	Mondaca S, Margolis M, Sanchez-Vega F, et al. PhaseⅡ study of trastuzumab with modified docetaxel, cisplatin, and 5 fluorouracil in metastatic HER2-positive gastric cancer. Gastric Cancer, 2019, 22(2): 355-362.
16.	Liu T, Qin Y, Li J, et al. Pertuzumab in combination with trastuzumab and chemotherapy for Chinese patients with HER2-positive metastatic gastric or gastroesophageal junction cancer: a subpopulation analysis of the JACOB trial. Cancer Commun (Lond), 2019, 39(1): 38.
17.	Janjigian YY, Kawazoe A, Yañez P, et al. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature, 2021, 600(7890): 727-730.
18.	Lin NU. Tucatinib plus trastuzumab and capecitabine for ERBB2 (HER2)-positive metastatic breast cancer with brain metastases-reply. JAMA Oncol, 2023, 9(7): 1009.
19.	Strickler J, Cercek A, Siena S, et al. LBA-2 primary analysis of MOUNTAINEER: a phase 2 study of tucatinib and trastuzumab for HER2-positive mCRC. Ann Oncol, 2022, 33: S375-S376. https://www.annalsofoncology.org/article/S0923-7534(22)01130-9/fulltext.
20.	Strickler JH, Nakamura Y, Yoshino T, et al. MOUNTAINEER-02: phaseⅡ/Ⅲ study of tucatinib, trastuzumab, ramucirumab, and paclitaxel in previously treated HER2⁺ gastric or gastroesophageal junction adenocarcinoma—trial in progress. J Clin Oncol, 2021, 39(3 Suppl): TPS252-TPS252.
21.	罗蒙, 许春景, 孙雨婷, 等. HER2阳性乳腺癌的靶向治疗及其耐药机制. 实用肿瘤杂志, 2018, 33(3): 283-288.
22.	Satoh T, Xu RH, Chung HC, et al. Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN— a randomized, phase Ⅲ study. J Clin Oncol, 2014, 32(19): 2039-2049.
23.	Mishima S, Shitara K. Trastuzumab deruxtecan for the treatment of HER2-positive gastric cancer. Expert Opin Biol Ther, 2021, 21(7): 825-830.
24.	Shitara K, Iwata H, Takahashi S, et al. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study. Lancet Oncol, 2019, 20(6): 827-836.
25.	Van Cutsem E, di Bartolomeo M, Smyth E, et al. Trastuzumab deruxtecan in patients in the USA and Europe with HER2-positive advanced gastric or gastroesophageal junction cancer with disease progression on or after a trastuzumab-containing regimen (DESTINY-Gastric02): primary and updated analyses from a single-arm, phase 2 study. Lancet Oncol, 2023, 24(7): 744-756.
26.	Yamaguchi K, Bang YJ, Iwasa S, et al. 1422MO trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-low, advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: results of the exploratory cohorts in the phaseⅡ, multicenter, open-label DESTINY-Gastric01 study. Ann Oncol, 2020, 31: S899-S900. https://www.annalsofoncology.org/article/S0923-7534(20)41924-6/fulltext.
27.	Xu Y, Wang Y, Gong J, et al. PhaseⅠstudy of the recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate RC48-ADC in patients with HER2-positive advanced solid tumors. Gastric Cancer, 2021, 24(4): 913-925.
28.	Ono H, Takeuchi Y, Ukegawa J, et al. Increased tyrosine kinase activites may lead to the phenotypic differences of gastric cancer cells. Anticancer Res, 2004, 24(2B): 699-705.
29.	Blanchet A, Bourgmayer A, Kurtz JE, et al. Isoforms of the p53 family and gastric cancer: a ménage à trois for an unfinished affair. Cancers (Basel), 2021, 13(4): 916.
30.	Espinoza LA, Tone LG, Neto JB, et al. Enhanced TGFalpha-EGFR expression and P53 gene alterations contributes to gastric tumors aggressiveness. Cancer Lett, 2004, 212(1): 33-41.
31.	Sullivan B, Light T, Vu V, et al. Mechanical disruption of E-cadherin complexes with epidermal growth factor receptor actuates growth factor-dependent signaling. Proc Natl Acad Sci U S A. 2022, 119(4): e2100679119. doi: 10.1073/pnas.2100679119.
32.	Moghbeli M, Makhdoumi Y, Soltani Delgosha M, et al. ErbB1 and ErbB3 co-over expression as a prognostic factor in gastric cancer. Biol Res, 2019, 52(1): 2.
33.	Mimori K, Nagahara H, Sudo T, et al. The epidermal growth factor receptor gene sequence is highly conserved in primary gastric cancers. J Surg Oncol, 2006, 93(1): 44-46.
34.	Qiu MZ, Zhang Y, Guo Y, et al. Evaluation of safety of treatment with anti-epidermal growth factor receptor antibody drug conjugate MRG003 in patients with advanced solid tumors: a phaseⅠnonrandomized clinical trial. JAMA Oncol, 2022, 8(7): 1042-1046.
35.	Yu J, Fang T, Yun C, et al. Antibody-drug conjugates targeting the human epidermal growth factor receptor family in cancers. Front Mol Biosci, 2022, 9: 847835.
36.	Saito-Adachi M, Hama N, Totoki Y, et al. Oncogenic structural aberration landscape in gastric cancer genomes. Nat Commun, 2023, 14(1): 3688.
37.	Yoshida K, Yasui W, Yokozaki H, et al. New molecular prognostic markers in gastric carcinoma. Gan To Kagaku Ryoho, 1998, 25(13): 2021-2027.
38.	Pavlakis N, Sjoquist KM, Martin AJ, et al. Regorafenib for the treatment of advanced gastric cancer (INTEGRATE): a multinational placebo-controlled phaseⅡ trial. J Clin Oncol, 2016, 34(23): 2728-2735.
39.	Ooki A, Yamaguchi K. The beginning of the era of precision medicine for gastric cancer with fibroblast growth factor receptor 2 aberration. Gastric Cancer, 2021, 24(6): 1169-1183.
40.	Hayashi H, Makiyama A, Okumura N, et al. Gastric carcinosarcoma with FGFR2 amplification under long-term control with pazopanib: a case report and literature review. BMC Gastroenterol, 2022, 22(1): 360.
41.	Quinzii A, Zecchetto C, Casalino S, et al. Clinical response to futibatinib in patients with high-level FGFR2-amplified advanced gastric cancer: two case reports. Clin Drug Investig, 2022, 42(8): 697-701.
42.	Xiang H, Liu L, Gao Y, et al. Population pharmacokinetic analysis of phase 1 bemarituzumab data to support phase 2 gastro-esophageal adenocarcinoma FIGHT trial. Cancer Chemother Pharmacol, 2020, 86(5): 595-606.
43.	Tsimafeyeu I, Statsenko G, Vladimirova L, et al. A phaseⅠb study of the allosteric extracellular FGFR2 inhibitor alofanib in patients with pretreated advanced gastric cancer. Invest New Drugs, 2023, 41(2): 324-332.
44.	Wu Z, Wang W, Zhang K, et al. Epigenetic and tumor microenvironment for prognosis of patients with gastric cancer. Biomolecules, 2023, 13(5): 736.
45.	Gherardi E, Birchmeier W, Birchmeier C, et al. Targeting MET in cancer: rationale and progress. Nat Rev Cancer, 2012, 12(2): 89-103.
46.	Toiyama Y, Yasuda H, Saigusa S, et al. Co-expression of hepatocyte growth factor and c-Met predicts peritoneal dissemination established by autocrine hepatocyte growth factor/c-Met signaling in gastric cancer. Int J Cancer, 2012, 130(12): 2912-2921.
47.	Zhang H, Deng T, Liu R, et al. Exosome-delivered EGFR regulates liver microenvironment to promote gastric cancer liver metastasis. Nat Commun, 2017, 8: 15016.
48.	Ding X, Ji J, Jiang J, et al. HGF-mediated crosstalk between cancer-associated fibroblasts and MET-unamplified gastric cancer cells activates coordinated tumorigenesis and metastasis. Cell Death Dis, 2018, 9(9): 867.
49.	Zhu M, Tang R, Doshi S, et al. Exposure-response analysis of rilotumumab in gastric cancer: the role of tumour MET expression. Br J Cancer, 2015, 112(3): 429-437.
50.	Yan SB, Um SL, Peek VL, et al. MET-targeting antibody (emibetuzumab) and kinase inhibitor (merestinib) as single agent or in combination in a cancer model bearing MET exon 14 skipping. Invest New Drugs, 2018, 36(4): 536-544.
51.	Shah MA, Bang YJ, Lordick F, et al. Effect of fluorouracil, leucovorin, and oxaliplatin with or without onartuzumab in HER2-negative, MET-positive gastroesophageal adenocarcinoma: the METgastric randomized clinical trial. JAMA Oncol, 2017, 3(5): 620-627.
52.	Ma JA, Hu C, Li W, et al. Downregulation of c-Met expression does not enhance the sensitivity of gastric cancer cell line MKN-45 to gefitinib. Mol Med Rep, 2015, 11: 2269-2275.
53.	Yang Y, Wu N, Shen J, MET overexpression and amplification define a distinct molecular subgroup for targeted therapies in gastric cancer. Gastric Cancer, 2016, 19(3): 778-788.
54.	Kim BJ, Kim YJ, Sohn SH, et al. Tivantinib inhibits the VEGF signaling pathway and induces apoptosis in gastric cancer cells with c-MET or VEGFA amplification. Invest New Drugs, 2020, 38(6): 1633-1640.
55.	Wang C, Li J, Qu L, et al. Discovery of D6808, a highly selective and potent macrocyclic c-Met inhibitor for gastric cancer harboring MET gene alteration treatment. J Med Chem, 2022, 65(22): 15140-15164.
56.	Patrad E, Khalighfard S, Amiriani T, et al. Molecular mechanisms underlying the action of carcinogens in gastric cancer with a glimpse into targeted therapy. Cell Oncol (Dordr), 2022, 45(6): 1073-1117.
57.	黄荧, 魏嘉, 刘宝瑞. K-ras突变在胃癌预后及靶向治疗中的研究进展. 中华肿瘤杂志, 2016, 38(2): 81-85.
58.	Yoshida K, Hamatani K, Koide H, et al. Preparation of anti-ras Mr 21 000 protein monoclonal antibodies and immunohistochemical analyses on expression of ras genes in human stomach and thyroid cancers. Cancer Res, 1988, 48(19): 5503-5509.
59.	于君, 张锦坤. 胃癌变过程ras基因活化和DNA含量的综合研究. 中华内科杂志, 1995, 34(11): 739-742.
60.	Song JJ, Lee H, Kim E, et al. Transduction effect of antisense K-ras on malignant phenotypes in gastric cancer cells. Cancer Lett, 2000, 157(1): 1-7.
61.	Li M, Liu W, Zhu YF, et al. Correlation of COX-2 and K-ras expression to clinical outcome in gastric cancer. Acta Oncol, 2006, 45(8): 1115-1119.
62.	Koga T, Suda K, Fujino T, et al. KRAS secondary mutations that confer acquired resistance to KRAS G12C inhibitors, sotorasib and adagrasib, and overcoming strategies: insights from in vitro experiments. J Thorac Oncol, 2021, 16(8): 1321-1332.

1. Siegel RL, Miller KD, Fuchs HE, et al. Cancer Statistics, 2021. CA Cancer J Clin, 2021, 71(1): 7-33.
2. Chen Y, Chen T, Fang JY. Burden of gastrointestinal cancers in China from 1990 to 2019 and projection through 2029. Cancer Lett, 2023, 560: 216127.
3. Sun D, Li H, Cao M, et al. Cancer burden in China: trends, risk factors and prevention. Cancer Biol Med, 2020, 17(4): 879-895.
4. Pihlak R, Fong C, Starling N. Targeted therapies and developing precision medicine in gastric cancer. Cancers (Basel), 2023, 15(12): 3248.
5. Joshi SS, Badgwell BD. Current treatment and recent progress in gastric cancer. CA Cancer J Clin, 2021, 71(3): 264-279.
6. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature, 2014, 513(7517): 202-209.
7. Deng N, Goh LK, Wang H, et al. A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut, 2012, 61(5): 673-684.
8. Lv Q, Meng Z, Yu Y, et al. Molecular mechanisms and translational therapies for human epidermal receptor 2 positive breast cancer. Int J Mol Sci, 2016, 7(12): 2095.
9. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet, 2010, 376(9742): 687-697.
10. Wagner AD, Grabsch HI, Mauer M, et al. EORTC-1203-GITCG— the “INNOVATION”-trial: effect of chemotherapy alone versus chemotherapy plus trastuzumab, versus chemotherapy plus trastuzumab plus pertuzumab, in the perioperative treatment of HER2 positive, gastric and gastroesophageal junction adenocarcinoma on pathologic response rate: a randomized phaseⅡ-intergroup trial of the EORTC-Gastrointestinal Tract Cancer Group, Korean Cancer Study Group and Dutch Upper GI-Cancer group. BMC Cancer, 2019, 19(1): 494.
11. Gong J, Liu T, Fan Q, et al. Optimal regimen of trastuzumab in combination with oxaliplatin/ capecitabine in first-line treatment of HER2-positive advanced gastric cancer (CGOG1001): a multicenter, phaseⅡ trial. BMC Cancer, 2016, 16: 68.
12. 叶春, 祁兴顺, 李谦谦, 等. XELOX联合曲妥珠单抗在HER2阳性老年晚期胃癌转化治疗中的疗效观察. 中国普外基础与临床杂志, 2022, 29(12): 1623-1627.
13. Kurokawa Y, Sugimoto N, Miwa H, et al. PhaseⅡstudy of trastuzumab in combination with S-1 plus cisplatin in HER2-positive gastric cancer (HERBIS-1). Br J Cancer, 2014, 110(5): 1163-1168.
14. Kagawa S, Muraoka A, Kambara T, et al. A multi-institution phaseⅡstudy of docetaxel and S-1 in combination with trastuzumab for HER2-positive advanced gastric cancer (DASH study). Cancer Chemother Pharmacol, 2018, 81(2): 387-392.
15. Mondaca S, Margolis M, Sanchez-Vega F, et al. PhaseⅡ study of trastuzumab with modified docetaxel, cisplatin, and 5 fluorouracil in metastatic HER2-positive gastric cancer. Gastric Cancer, 2019, 22(2): 355-362.
16. Liu T, Qin Y, Li J, et al. Pertuzumab in combination with trastuzumab and chemotherapy for Chinese patients with HER2-positive metastatic gastric or gastroesophageal junction cancer: a subpopulation analysis of the JACOB trial. Cancer Commun (Lond), 2019, 39(1): 38.
17. Janjigian YY, Kawazoe A, Yañez P, et al. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature, 2021, 600(7890): 727-730.
18. Lin NU. Tucatinib plus trastuzumab and capecitabine for ERBB2 (HER2)-positive metastatic breast cancer with brain metastases-reply. JAMA Oncol, 2023, 9(7): 1009.
19. Strickler J, Cercek A, Siena S, et al. LBA-2 primary analysis of MOUNTAINEER: a phase 2 study of tucatinib and trastuzumab for HER2-positive mCRC. Ann Oncol, 2022, 33: S375-S376. https://www.annalsofoncology.org/article/S0923-7534(22)01130-9/fulltext.
20. Strickler JH, Nakamura Y, Yoshino T, et al. MOUNTAINEER-02: phaseⅡ/Ⅲ study of tucatinib, trastuzumab, ramucirumab, and paclitaxel in previously treated HER2⁺ gastric or gastroesophageal junction adenocarcinoma—trial in progress. J Clin Oncol, 2021, 39(3 Suppl): TPS252-TPS252.
21. 罗蒙, 许春景, 孙雨婷, 等. HER2阳性乳腺癌的靶向治疗及其耐药机制. 实用肿瘤杂志, 2018, 33(3): 283-288.
22. Satoh T, Xu RH, Chung HC, et al. Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN— a randomized, phase Ⅲ study. J Clin Oncol, 2014, 32(19): 2039-2049.
23. Mishima S, Shitara K. Trastuzumab deruxtecan for the treatment of HER2-positive gastric cancer. Expert Opin Biol Ther, 2021, 21(7): 825-830.
24. Shitara K, Iwata H, Takahashi S, et al. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study. Lancet Oncol, 2019, 20(6): 827-836.
25. Van Cutsem E, di Bartolomeo M, Smyth E, et al. Trastuzumab deruxtecan in patients in the USA and Europe with HER2-positive advanced gastric or gastroesophageal junction cancer with disease progression on or after a trastuzumab-containing regimen (DESTINY-Gastric02): primary and updated analyses from a single-arm, phase 2 study. Lancet Oncol, 2023, 24(7): 744-756.
26. Yamaguchi K, Bang YJ, Iwasa S, et al. 1422MO trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-low, advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: results of the exploratory cohorts in the phaseⅡ, multicenter, open-label DESTINY-Gastric01 study. Ann Oncol, 2020, 31: S899-S900. https://www.annalsofoncology.org/article/S0923-7534(20)41924-6/fulltext.
27. Xu Y, Wang Y, Gong J, et al. PhaseⅠstudy of the recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate RC48-ADC in patients with HER2-positive advanced solid tumors. Gastric Cancer, 2021, 24(4): 913-925.
28. Ono H, Takeuchi Y, Ukegawa J, et al. Increased tyrosine kinase activites may lead to the phenotypic differences of gastric cancer cells. Anticancer Res, 2004, 24(2B): 699-705.
29. Blanchet A, Bourgmayer A, Kurtz JE, et al. Isoforms of the p53 family and gastric cancer: a ménage à trois for an unfinished affair. Cancers (Basel), 2021, 13(4): 916.
30. Espinoza LA, Tone LG, Neto JB, et al. Enhanced TGFalpha-EGFR expression and P53 gene alterations contributes to gastric tumors aggressiveness. Cancer Lett, 2004, 212(1): 33-41.
31. Sullivan B, Light T, Vu V, et al. Mechanical disruption of E-cadherin complexes with epidermal growth factor receptor actuates growth factor-dependent signaling. Proc Natl Acad Sci U S A. 2022, 119(4): e2100679119. doi: 10.1073/pnas.2100679119.
32. Moghbeli M, Makhdoumi Y, Soltani Delgosha M, et al. ErbB1 and ErbB3 co-over expression as a prognostic factor in gastric cancer. Biol Res, 2019, 52(1): 2.
33. Mimori K, Nagahara H, Sudo T, et al. The epidermal growth factor receptor gene sequence is highly conserved in primary gastric cancers. J Surg Oncol, 2006, 93(1): 44-46.
34. Qiu MZ, Zhang Y, Guo Y, et al. Evaluation of safety of treatment with anti-epidermal growth factor receptor antibody drug conjugate MRG003 in patients with advanced solid tumors: a phaseⅠnonrandomized clinical trial. JAMA Oncol, 2022, 8(7): 1042-1046.
35. Yu J, Fang T, Yun C, et al. Antibody-drug conjugates targeting the human epidermal growth factor receptor family in cancers. Front Mol Biosci, 2022, 9: 847835.
36. Saito-Adachi M, Hama N, Totoki Y, et al. Oncogenic structural aberration landscape in gastric cancer genomes. Nat Commun, 2023, 14(1): 3688.
37. Yoshida K, Yasui W, Yokozaki H, et al. New molecular prognostic markers in gastric carcinoma. Gan To Kagaku Ryoho, 1998, 25(13): 2021-2027.
38. Pavlakis N, Sjoquist KM, Martin AJ, et al. Regorafenib for the treatment of advanced gastric cancer (INTEGRATE): a multinational placebo-controlled phaseⅡ trial. J Clin Oncol, 2016, 34(23): 2728-2735.
39. Ooki A, Yamaguchi K. The beginning of the era of precision medicine for gastric cancer with fibroblast growth factor receptor 2 aberration. Gastric Cancer, 2021, 24(6): 1169-1183.
40. Hayashi H, Makiyama A, Okumura N, et al. Gastric carcinosarcoma with FGFR2 amplification under long-term control with pazopanib: a case report and literature review. BMC Gastroenterol, 2022, 22(1): 360.
41. Quinzii A, Zecchetto C, Casalino S, et al. Clinical response to futibatinib in patients with high-level FGFR2-amplified advanced gastric cancer: two case reports. Clin Drug Investig, 2022, 42(8): 697-701.
42. Xiang H, Liu L, Gao Y, et al. Population pharmacokinetic analysis of phase 1 bemarituzumab data to support phase 2 gastro-esophageal adenocarcinoma FIGHT trial. Cancer Chemother Pharmacol, 2020, 86(5): 595-606.
43. Tsimafeyeu I, Statsenko G, Vladimirova L, et al. A phaseⅠb study of the allosteric extracellular FGFR2 inhibitor alofanib in patients with pretreated advanced gastric cancer. Invest New Drugs, 2023, 41(2): 324-332.
44. Wu Z, Wang W, Zhang K, et al. Epigenetic and tumor microenvironment for prognosis of patients with gastric cancer. Biomolecules, 2023, 13(5): 736.
45. Gherardi E, Birchmeier W, Birchmeier C, et al. Targeting MET in cancer: rationale and progress. Nat Rev Cancer, 2012, 12(2): 89-103.
46. Toiyama Y, Yasuda H, Saigusa S, et al. Co-expression of hepatocyte growth factor and c-Met predicts peritoneal dissemination established by autocrine hepatocyte growth factor/c-Met signaling in gastric cancer. Int J Cancer, 2012, 130(12): 2912-2921.
47. Zhang H, Deng T, Liu R, et al. Exosome-delivered EGFR regulates liver microenvironment to promote gastric cancer liver metastasis. Nat Commun, 2017, 8: 15016.
48. Ding X, Ji J, Jiang J, et al. HGF-mediated crosstalk between cancer-associated fibroblasts and MET-unamplified gastric cancer cells activates coordinated tumorigenesis and metastasis. Cell Death Dis, 2018, 9(9): 867.
49. Zhu M, Tang R, Doshi S, et al. Exposure-response analysis of rilotumumab in gastric cancer: the role of tumour MET expression. Br J Cancer, 2015, 112(3): 429-437.
50. Yan SB, Um SL, Peek VL, et al. MET-targeting antibody (emibetuzumab) and kinase inhibitor (merestinib) as single agent or in combination in a cancer model bearing MET exon 14 skipping. Invest New Drugs, 2018, 36(4): 536-544.
51. Shah MA, Bang YJ, Lordick F, et al. Effect of fluorouracil, leucovorin, and oxaliplatin with or without onartuzumab in HER2-negative, MET-positive gastroesophageal adenocarcinoma: the METgastric randomized clinical trial. JAMA Oncol, 2017, 3(5): 620-627.
52. Ma JA, Hu C, Li W, et al. Downregulation of c-Met expression does not enhance the sensitivity of gastric cancer cell line MKN-45 to gefitinib. Mol Med Rep, 2015, 11: 2269-2275.
53. Yang Y, Wu N, Shen J, MET overexpression and amplification define a distinct molecular subgroup for targeted therapies in gastric cancer. Gastric Cancer, 2016, 19(3): 778-788.
54. Kim BJ, Kim YJ, Sohn SH, et al. Tivantinib inhibits the VEGF signaling pathway and induces apoptosis in gastric cancer cells with c-MET or VEGFA amplification. Invest New Drugs, 2020, 38(6): 1633-1640.
55. Wang C, Li J, Qu L, et al. Discovery of D6808, a highly selective and potent macrocyclic c-Met inhibitor for gastric cancer harboring MET gene alteration treatment. J Med Chem, 2022, 65(22): 15140-15164.
56. Patrad E, Khalighfard S, Amiriani T, et al. Molecular mechanisms underlying the action of carcinogens in gastric cancer with a glimpse into targeted therapy. Cell Oncol (Dordr), 2022, 45(6): 1073-1117.
57. 黄荧, 魏嘉, 刘宝瑞. K-ras突变在胃癌预后及靶向治疗中的研究进展. 中华肿瘤杂志, 2016, 38(2): 81-85.
58. Yoshida K, Hamatani K, Koide H, et al. Preparation of anti-ras Mr 21 000 protein monoclonal antibodies and immunohistochemical analyses on expression of ras genes in human stomach and thyroid cancers. Cancer Res, 1988, 48(19): 5503-5509.
59. 于君, 张锦坤. 胃癌变过程ras基因活化和DNA含量的综合研究. 中华内科杂志, 1995, 34(11): 739-742.
60. Song JJ, Lee H, Kim E, et al. Transduction effect of antisense K-ras on malignant phenotypes in gastric cancer cells. Cancer Lett, 2000, 157(1): 1-7.
61. Li M, Liu W, Zhu YF, et al. Correlation of COX-2 and K-ras expression to clinical outcome in gastric cancer. Acta Oncol, 2006, 45(8): 1115-1119.
62. Koga T, Suda K, Fujino T, et al. KRAS secondary mutations that confer acquired resistance to KRAS G12C inhibitors, sotorasib and adagrasib, and overcoming strategies: insights from in vitro experiments. J Thorac Oncol, 2021, 16(8): 1321-1332.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Advances in molecular mechanisms and targeted therapy of gastric cancer associated withthe RTK/RAS signaling pathway

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