Abstract 3309: Co-inhibition of ALK and EGFR and/or c-MET on cell growth and response to radiation in ALK-positive NSCLC cells

Abstract

Abstract ALK (anaplastic lymphoma kinase), EGFR (epidermal growth factor receptor) and c-MET are molecular drivers for a subset of non-small cell lung cancers (NSCLC). Approximately 4-7% of NSCLCs carry the EML4-ALK chromosomal rearrangement. We identified overexpression of EGFR and c-MET in EML4-ALK-positive NSCLC cell lines H3122 and H2228. ALK, EGFR, and c-MET may function cooperatively to modulate tumor growth, stress response, and survival in EML4-ALK-positive cells and co-inhibition may favorably impact tumor control. We therefore investigated the effects of co-inhibition of ALK and EGFR or c-MET on cell survival and response to radiation in EML4-ALK-positive NSCLC cells. Compared with ALK-negative cell lines (H226, A549 and H520), the ALK-positive cell lines (H3122, H2228) were highly sensitive to the ALK inhibitors crizotinb, ceritinib and alectinib, although with differing sensitivity to radiation. Crizotinib, ceritinib and alectinib sensitized H3122 and H2228 to radiation, as evaluated by clonogenic assay. However, knockdown of ALK by siRNA in H3122 and H2228, or overexpression of EML4-ALK in NIH-3T3 cells, had only moderate effects on radiosensitivity. Simultaneous knockdown of ALK and MET, or ALK and EGFR, increased radiosensitivity as assessed by clonogenic survival in H3122 and H2228 cells, while also increasing inhibitory effects on cell growth and proliferation. These results were confirmed in cells treated with the combination of ceritinib and su11274 (c-MET inhibitor) or with ceritinib and erlotinib (EGFR inhibitor). We further assessed the impact of drug alone or in combination with radiation on cell cycle, cell survival and DNA damage repair pathways. To further evaluate ALK function in the cellular response to radiation in NSCLC, we are developing EML4-ALK stable expression cell lines. Evaluation of drug-radiation interactions in xenograft model systems are also under consideration. These data indicate that co-inhibition of ALK and EGFR or c-MET can enhance growth inhibitory effects in ALK-positive cells and augment radiosensitivity in-vitro, suggesting the potential value for ALK inhibitors combined with EGFR/c-MET-targeting for therapeutic benefit in ALK-positive NSCLC patients with or without radiation. Citation Format: Chunrong Li, Shyhmin Huang, Fang Ma, Eric A. Armstrong, David Francis, Lauryn Werner, Paul M. Harari. Co-inhibition of ALK and EGFR and/or c-MET on cell growth and response to radiation in ALK-positive NSCLC cells. [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 3309. doi:10.1158/1538-7445.AM2015-3309