ALK inhibitor and chemotherapy combinations in ALK translocated NSCLC models

Abstract

Abstract Background Randomized trials have shown a benefit of combining TKI and chemotherapy in the treatment of EGFR mutant non-small cell lung cancer (NSCLC). In ALK + NSCLC, prospective trial results of the combination are not available, and this has not thoroughly been investigated in vitro. In this study, we investigated TKI and chemotherapy combinations using in vitro models of ALK + NSCLC. Materials and Methods We used ALK + cell line models H3122, H2228 and DFCI032 with variable sensitivity to ALK cTKIs. We investigated short (MTS assay) and long-term (colony formation) cytotoxicity, apoptosis and cell signaling in response to combinations. We selected the most commonly clinical used agents alectinib, cisplatin, and pemetrexed to investigate the combination effects. Results In the combination experiments with short-term exposure, synergism between TKI and pemetrexed was seen while cisplatin had antagonistic effects. In the long-term experiments, cisplatin and TKI had synergism in all the lines while no synergism was observed with pemetrexed. Of the chemotherapy and TKI sequence, cisplatin followed by TKI was more cytotoxic than the opposite in two out of three models. In the TKI sensitive H3122 cell line, chemotherapy and TKI combination increased apoptosis. Interestingly, pemetrexed treatment resulted in activation of ALK which could be abolished with TKI. Conclusions Combining TKI and chemotherapy in ALK + models have some potential synergistic effects. However, the synergy varies on the used chemotherapeutic agent, used cytotoxic assay, and tested cell line. Prospective clinical trials are warranted to fully characterize the potential of combination chemotherapy to TKIs in ALK + NSCLC.