Individual dose and scheduling determine the efficacy of combining cytotoxic anticancer agents with a kinase inhibitor in non-small-cell lung cancer

Abstract

To investigate the combination of conventional cytotoxic anticancer agents and a small molecule kinase inhibitor in preclinical models of non-small-cell lung cancer (NSCLC). We compared the induction of apoptosis by DNA-damaging anticancer drugs and PKC412, a predominantly protein kinase C (PKC)-specific small molecule inhibitor, in six NSCLC cell lines of different histologic and genetic backgrounds. The outcome of various combinations and schedules of DNA-damaging agents and PKC412 was studied, and isobolograms were calculated. Conditional expression of pro-apoptotic BAK was applied to specifically target apoptotic signal transduction in combination with drug therapy. Resistance of NSCLC cells to DNA damage-induced apoptosis was mainly determined at the mitochondrial step of the intrinsic pathway of caspase activation. PKC412 effectively inhibited the growth factor signal transduction, but failed to induce apoptosis in NSCLC cells resistant to DNA-damaging agents. Combining conventional anticancer drugs with PKC412 at different doses and schedules resulted in unpredictable outcomes, including synergistic, additive, and antagonistic interactions. In contrast, conditional expression of BAK reliably sensitized drug-resistant NSCLC cells to apoptosis induced by cytotoxic agents or PKC412. Combining DNA-damaging anticancer drugs with a pharmacologic inhibitor of growth and survival factor signaling in NSCLC may result in unpredictable treatment outcomes. In contrast, targeting specific death effector mechanisms, such as apoptotic signal transduction, is a promising strategy to sensitize NSCLC to cytotoxic agents or kinase inhibitors.