Autophagy plays an important role in the response of tumors to environmental stress including colorectal cancer (CRC). The present study aimed to investigate the relationship between the autophagic capacities of CRC cells and their sensitivities to Nintedanib and Regorafenib, two TKIs with clinical activity in metastatic CRC. Our results showed various effects of these two TKIs on cell viability across a panel consisting of 12 well-characterized CRC cell lines. We showed an opposite cytotoxicity profile between HT-29 and LoVo cell lines for both TKIs which is accompanied by an induction of autophagy in cell-type and drug-dependent manner. Interestingly, pharmacologic and genetic autophagy inhibition decreased the cytotoxic activity of Nintedanib but did not affect the activity of Regorafenib. In addition, signaling pathways analysis revealed opposing effects on the Akt-mTOR and Erk-signaling pathways by the two TKIs. Nintedanib inhibits the Akt- mTOR pathway which is compensated by activation of Erk signaling, whereas Regorafenib is a strong inhibitor of Erk-signaling and is accompanied by Akt- mTOR activation. Taken together, our results indicate that autophagy contributes to the cytotoxic activity of Nintedanib but not that of Regorafenib. These results highlighted that CRC with high autophagic flux may be selectively sensitive to Nintedanib.
Louadj et al. (Sat,) studied this question.