Hedgehog signalling is involved in acquired resistance to KRASG12C inhibitors in lung cancer cells

Abstract

Although KRAS^G12C inhibitors have shown promising activity in lung adenocarcinomas harbouring KRAS^G12C, acquired resistance to these therapies eventually occurs in most patients. Re-expression of KRAS is thought to be one of the main causes of acquired resistance. However, the mechanism through which cancer cells re-express KRAS is not fully understood. Here, we report that the Hedgehog signal is induced by KRAS^G12C inhibitors and mediates KRAS re-expression in cancer cells treated with a KRAS^G12C inhibitor. Further, KRAS^G12C inhibitors induced the formation of primary cilia and activated the Hedgehog-GLI-1 pathway. GLI-1 binds to the KRAS promoter region, enhancing KRAS promoter activity and KRAS expression. Inhibition of GLI using siRNA or the smoothened (Smo) inhibitor suppressed re-expression of KRAS in cells treated with a KRAS^G12C inhibitor. In addition, we demonstrate that KRAS^G12C inhibitors decreased Aurora kinase A (AURKA) levels in cancer cells, and inhibition of AURKA using siRNA or inhibitors led to increased expression levels of GLI-1 and KRAS even in the absence of KRAS inhibitor. Ectopic expression of AURKA attenuated the effect of KRAS^G12C inhibitors on the expression of GLI-1 and re-expression of KRAS. Together, these findings demonstrate the important role of AURKA, primary cilia, and Hedgehog signals in the re-expression of KRAS and therefore the induction of acquired resistance to KRAS^G12C inhibitors, and provide a rationale for targeting Hedgehog signalling to overcome acquired resistance to KRAS^G12C inhibitors.