Effects of Trastuzumab and Afatinib on Kinase Activity in Gastric Cancer Cell Lines

Overview

Journal Mol Oncol

Specialties Molecular Biology
Oncology

Date 2018 Jan 12

PMID 29325228

Citations 14

Authors

Simone Keller

Gwen Zwingenberger

Karolin Ebert

Jan Hasenauer

Jacqueline Wasmuth

Dieter Maier

Ivonne Haffner

Katrin Schierle

Gregor Weirich

Birgit Luber

Affiliations

Soon will be listed here.

Abstract

The molecular mechanism of action of the HER2-targeted antibody trastuzumab is only partially understood, and the direct effects of trastuzumab on the gastric cancer signaling network are unknown. In this study, we compared the molecular effect of trastuzumab and the HER kinase inhibitor afatinib on the receptor tyrosine kinase (RTK) network and the downstream-acting intracellular kinases in gastric cancer cell lines. The molecular effects of trastuzumab and afatinib on the phosphorylation of 49 RTKs and 43 intracellular kinase phosphorylation sites were investigated in three gastric cancer cell lines (NCI-N87, MKN1, and MKN7) using proteome profiling. To evaluate these effects, data were analyzed using mixed models and clustering. Moreover, proliferation assays were performed. Our comprehensive quantitative analysis of kinase activity in gastric cancer cell lines indicates that trastuzumab and afatinib selectively influenced the HER family RTKs. The effects of trastuzumab differed between cell lines, depending on the presence of activated HER2. The effects of trastuzumab monotherapy were not transduced to the intracellular kinase network. Afatinib alone or in combination with trastuzumab influenced HER kinases in all cell lines; that is, the effects of monotherapy and combination therapy were transduced to the intracellular kinase network. These results were confirmed by proliferation analysis. Additionally, the MET-amplified cell line Hs746T was identified as afatinib nonresponder. The dependence of the effect of trastuzumab on the presence of activated HER2 might explain the clinical nonresponse of some patients who are routinely tested for HER2 expression and gene amplification in the clinic but not for HER2 activation. The consistent effects of afatinib on HER RTKs and downstream kinase activation suggest that afatinib might be an effective candidate in the future treatment of patients with gastric cancer irrespective of the presence of activated HER2. However, MET amplification should be taken into account as potential resistance factor.

Citing Articles

Prognostic value of RNA methylation-related genes in gastric adenocarcinoma based on bioinformatics.

He X, Chen X, Yang C, Wang W, Sun H, Wang J PeerJ. 2024; 12:e16951.

PMID: 38436027 PMC: 10909369. DOI: 10.7717/peerj.16951.

Quantitative proteomics profiling reveals the inhibition of trastuzumab antitumor efficacy by phosphorylated RPS6 in gastric carcinoma.

Hu C, Pei S, Wang J, Zu L, Shen W, Yuan L Cancer Chemother Pharmacol. 2023; 92(5):341-355.

PMID: 37507485 DOI: 10.1007/s00280-023-04571-2.

HER3 PET Imaging Predicts Response to Pan Receptor Tyrosine Kinase Inhibition Therapy in Gastric Cancer.

Esfahani S, de Aguiar Ferreira C, Rotile N, Ataeinia B, Krishna S, Catalano O Mol Imaging Biol. 2022; 25(2):353-362.

PMID: 35962301 PMC: 10024929. DOI: 10.1007/s11307-022-01763-9.

Hyperpolarized [1-C]Pyruvate Magnetic Resonance Spectroscopic Imaging for Evaluation of Early Response to Tyrosine Kinase Inhibition Therapy in Gastric Cancer.

Esfahani S, Callahan C, Rotile N, Heidari P, Mahmood U, Caravan P Mol Imaging Biol. 2022; 24(5):769-779.

PMID: 35467249 PMC: 9588528. DOI: 10.1007/s11307-022-01727-z.

Combining gene expression analysis of gastric cancer cell lines and tumor specimens to identify biomarkers for anti-HER therapies-the role of HAS2, SHB and HBEGF.

Ebert K, Haffner I, Zwingenberger G, Keller S, Raimundez E, Geffers R BMC Cancer. 2022; 22(1):254.

PMID: 35264144 PMC: 8908634. DOI: 10.1186/s12885-022-09335-4.

References

Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M . Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2014; 136(5):E359-86. DOI: 10.1002/ijc.29210. View

Turke A, Zejnullahu K, Wu Y, Song Y, Dias-Santagata D, Lifshits E . Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell. 2010; 17(1):77-88. PMC: 2980857. DOI: 10.1016/j.ccr.2009.11.022. View

Forbes S, Beare D, Gunasekaran P, Leung K, Bindal N, Boutselakis H . COSMIC: exploring the world's knowledge of somatic mutations in human cancer. Nucleic Acids Res. 2014; 43(Database issue):D805-11. PMC: 4383913. DOI: 10.1093/nar/gku1075. View

Hecht J, Bang Y, Qin S, Chung H, Xu J, Park J . Lapatinib in Combination With Capecitabine Plus Oxaliplatin in Human Epidermal Growth Factor Receptor 2-Positive Advanced or Metastatic Gastric, Esophageal, or Gastroesophageal Adenocarcinoma: TRIO-013/LOGiC--A Randomized Phase III Trial. J Clin Oncol. 2015; 34(5):443-51. DOI: 10.1200/JCO.2015.62.6598. View

Motoyama A, Hynes N, Lane H . The efficacy of ErbB receptor-targeted anticancer therapeutics is influenced by the availability of epidermal growth factor-related peptides. Cancer Res. 2002; 62(11):3151-8. View

Janjigian Y, Viola-Villegas N, Holland J, Divilov V, Carlin S, Gomes-DaGama E . Monitoring afatinib treatment in HER2-positive gastric cancer with 18F-FDG and 89Zr-trastuzumab PET. J Nucl Med. 2013; 54(6):936-43. PMC: 4967936. DOI: 10.2967/jnumed.112.110239. View

Sawabu T, Seno H, Kawashima T, Fukuda A, Uenoyama Y, Kawada M . Growth arrest-specific gene 6 and Axl signaling enhances gastric cancer cell survival via Akt pathway. Mol Carcinog. 2006; 46(2):155-64. DOI: 10.1002/mc.20211. View

Neve R, Lane H, Hynes N . The role of overexpressed HER2 in transformation. Ann Oncol. 2001; 12 Suppl 1:S9-13. DOI: 10.1093/annonc/12.suppl_1.s9. View

Zang Z, Ong C, Cutcutache I, Yu W, Zhang S, Huang D . Genetic and structural variation in the gastric cancer kinome revealed through targeted deep sequencing. Cancer Res. 2010; 71(1):29-39. PMC: 3719377. DOI: 10.1158/0008-5472.CAN-10-1749. View

10.

Debebe Z, Rathmell W . Ror2 as a therapeutic target in cancer. Pharmacol Ther. 2015; 150:143-8. PMC: 9236825. DOI: 10.1016/j.pharmthera.2015.01.010. View

11.

Bardelli A, Siena S . Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer. J Clin Oncol. 2010; 28(7):1254-61. DOI: 10.1200/JCO.2009.24.6116. View

12.

Wu S, Liu Y, Tsai M, Chang Y, Yu C, Yang P . The mechanism of acquired resistance to irreversible EGFR tyrosine kinase inhibitor-afatinib in lung adenocarcinoma patients. Oncotarget. 2016; 7(11):12404-13. PMC: 4914294. DOI: 10.18632/oncotarget.7189. View

13.

Majewski I, Nuciforo P, Mittempergher L, Bosma A, Eidtmann H, Holmes E . PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast cancer. J Clin Oncol. 2015; 33(12):1334-9. PMC: 5087318. DOI: 10.1200/JCO.2014.55.2158. View

14.

Yang W, Soares J, Greninger P, Edelman E, Lightfoot H, Forbes S . Genomics of Drug Sensitivity in Cancer (GDSC): a resource for therapeutic biomarker discovery in cancer cells. Nucleic Acids Res. 2012; 41(Database issue):D955-61. PMC: 3531057. DOI: 10.1093/nar/gks1111. View

15.

Ishida M, Kagawa S, Shimoyama K, Takehara K, Noma K, Tanabe S . Trastuzumab-Based Photoimmunotherapy Integrated with Viral HER2 Transduction Inhibits Peritoneally Disseminated HER2-Negative Cancer. Mol Cancer Ther. 2016; 15(3):402-11. PMC: 4783182. DOI: 10.1158/1535-7163.MCT-15-0644. View

16.

Green J, Nusse R, van Amerongen R . The role of Ryk and Ror receptor tyrosine kinases in Wnt signal transduction. Cold Spring Harb Perspect Biol. 2013; 6(2). PMC: 3941236. DOI: 10.1101/cshperspect.a009175. View

17.

Molina M, Saez R, Ramsey E, Garcia-Barchino M, Rojo F, Evans A . NH(2)-terminal truncated HER-2 protein but not full-length receptor is associated with nodal metastasis in human breast cancer. Clin Cancer Res. 2002; 8(2):347-53. View

18.

Liu Y, Shen D, Yin X, Gavine P, Zhang T, Su X . HER2, MET and FGFR2 oncogenic driver alterations define distinct molecular segments for targeted therapies in gastric carcinoma. Br J Cancer. 2014; 110(5):1169-78. PMC: 3950883. DOI: 10.1038/bjc.2014.61. View

19.

Zhao L, Yasumoto K, Kawashima A, Nakagawa T, Takeuchi S, Yamada T . Paracrine activation of MET promotes peritoneal carcinomatosis in scirrhous gastric cancer. Cancer Sci. 2013; 104(12):1640-6. PMC: 7653526. DOI: 10.1111/cas.12301. View

20.

Kuniyasu H, Yasui W, Kitadai Y, Yokozaki H, Ito H, Tahara E . Frequent amplification of the c-met gene in scirrhous type stomach cancer. Biochem Biophys Res Commun. 1992; 189(1):227-32. DOI: 10.1016/0006-291x(92)91548-5. View