Failure to induce apoptosis via BCL-2 family proteins underlies lack of efficacy of combined MEK and PI3K inhibitors for KRAS mutant lung cancers

摘要

Although several groups have demonstrated that concomitant use of MEK and PI3K inhibitors (MEKi/PI3Ki) can induce dramatic tumor regressions in mouse models of KRAS mutant non-small cell lung cancer (NSCLC), ongoing clinical trials investigating this strategy have been underwhelming to date. While efficacy may be hampered by a narrow therapeutic index, the contribution of biological heterogeneity in the response of KRAS mutant NSCLCs to MEKi/PI3Ki has been largely unexplored. In this study, we find that most human KRAS mutant NSCLC cell lines fail to undergo marked apoptosis in response to MEKi/PI3Ki, which is key for tumor responsiveness in vivo. This heterogeneity of apoptotic response occurs despite relatively uniform induction of growth arrest. Using a targeted shRNA screen of BCL-2 family members, we identify BIM, PUMA and BCL-XL as key regulators of the apoptotic response induced by MEKi/PI3Ki, with decreased expression of BIM and PUMA relative to BCL-XL in cell lines with intrinsic resistance. Additionally, by modeling adaptive resistance to MEKi/PI3Ki both in vitro and in vivo, we find that, upon the development of resistance, tumors have a diminished apoptotic response due to down-regulation of BIM and PUMA. These results suggest that the inability to induce apoptosis may limit the effectiveness of MEKi/PI3Ki for KRAS mutant NSCLC by contributing to intrinsic and adaptive resistance to this therapy.