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

ABSTRACT

Although KRASG12C inhibitors have shown promising activity in lung adenocarcinomas harbouring KRASG12C, 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 KRASG12C inhibitors and mediates KRAS re-expression in cancer cells treated with a KRASG12C inhibitor. Further, KRASG12C 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 KRASG12C inhibitor. In addition, we demonstrate that KRASG12C 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 KRASG12C 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 KRASG12C inhibitors, and provide a rationale for targeting Hedgehog signalling to overcome acquired resistance to KRASG12C inhibitors.