Abstract 3599: Resistance mechanisms to HER2-targeting treatment in HER2-positive gastric cancer

Background: HER2 is the first validated therapeutic target in advanced gastric cancer (GC). Trastuzumab in combination with chemotherapy is used as a first-line treatment of GC. The resistance mechanisms to trastuzumab have not been widely known in GC. We investigated the resistance mechanisms to HER2-targeting agents in HER2-positive gastric cancer cells. Methods: SNU216 and NCI-N87 are HER2 amplified gastric cancer cells. Using these cells, we established trastuzumab-resistant cells (SNU216-HR, N87-HR) and dacomitinib (panHER inhibitor)-resistant cells (SNU216-PR). Acquired resistance of the established cell lines was verified by MTT assay and western blotting. We compared various receptor tyrosine kinase activities and protein expression levels between parental and resistant cells by RTK arrays and western blotting. We used many targeted agents (HER family inhibitor, PI3K inhibitor, mTOR inhibitor, MEK inhibitor, Src inhibitor, HSP90 inhibitor, etc) to overcome the resistance. Results: Resistant cells displayed more rapid growth rate and different morphology compared with parent cells. Resistant cells showed increased levels of pEGFR, pHER2, pHER3, pMET, pIGF1R, pAXL, pSTAT3, pAKT, pFAK, and TS compared with the parental cells in western blot. With the treatment of trastuzumab, HR cells showed elevated levels of EGFR, pHER2, AXL, pAXL, pMEK, pSRC, pSTAT3, pAKT, pERK and TS compared with the parental cells. With the treatment of dacominitib, PR cells showed elevated levels of pEGFR, pAXL, pIGF1R, pMEK, pSRC, pERK and TS compared with the parental cells in western blot. The RTK arrays also showed the similar findings. These resistant cells were more sensitive to Src inhibitor and PI3K inhibitor than parent cells. Conclusion: Resistance mechanisms to HER2-targeting strategy in gastric cancer include activation of HER, MET, FAK and Src pathway. Targeting these pathways is needed to overcome resistance. Citation Format: Kyo Hwa Kang, Ah-Rong Nam, Ji Eun Park, Ju-Hee Bang, Jin Ling, Mei Hua Jin, Tae Yong Kim, Sae-Won Han, Sang-Hyun Song, Seock-Ah Im, Tae-You Kim, Do-Youn Oh, Yung-Jue Bang. Resistance mechanisms to HER2-targeting treatment in HER2-positive gastric cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3599. doi:10.1158/1538-7445.AM2015-3599