FBW7 mutations mediate resistance of colorectal cancer to targeted therapies by blocking Mcl-1 degradation

Abstract

Colorectal cancer (CRC), the second leading cause of cancer-related deaths in the US, has been treated with targeted therapies. However, the mechanisms of differential responses and resistance of CRCs to targeted therapies are not well understood. In this study, we found that genetic alterations of FBW7, an E3 ubiquitin ligase and a tumor suppressor frequently mutated in CRCs, contribute to resistance to targeted therapies. CRC cells containing FBW7 inactivating mutations are insensitive to clinically used multi-kinase inhibitors of RAS/RAF/MEK/ERK signaling, including regorafenib and sorafenib. In contrast, sensitivity to these agents is not affected by oncogenic mutations in KRAS, BRAF, PIK3CA, or p53. These cells are defective in apoptosis due to blocked degradation of Mcl-1, a pro-survival Bcl-2 family protein. Deleting FBW7 in FBW7-wild-type CRC cells abolishes Mcl-1 degradation and recapitulates the in vitro and in vivo drug resistance phenotypes of FBW7-mutant cells. CRC cells selected for regorafenib resistance have progressive enrichment of pre-existing FBW7 hotspot mutations, and are cross-resistant to other targeted drugs that induce Mcl-1 degradation. Furthermore, a selective Mcl-1 inhibitor restores regorafenib sensitivity in CRC cells with intrinsic or acquired resistance. Together, our results demonstrate FBW7 mutational status as a key genetic determinant of CRC response to targeted therapies, and Mcl-1 as an attractive therapeutic target.

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MicroRNA‐130b targets PTEN to induce resistance to cisplatin in lung cancer cells by activating Wnt/β‐catenin pathway

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FBW7-Dependent Mcl-1 Degradation Mediates the Anticancer Effect of Hsp90 Inhibitors

“…Our findings elucidate a critical functional role of FBW7 mutations and Mcl-1 stability in differential sensitivity and resistance of CRC cells to Hsp90 inhibition. Most of the FBW7 mutations in CRCs are heterozygous point mutations (29). Mutant FBW7 may have altered protein stability, or act as dominant negative proteins upon hetero-dimerization with WT FBW7 (23).…”

“…Studies by us and other groups showed that p53 mutational status influences 17-AAG sensitivity through the effects on p53 downstream targets including PUMA, Bax, Bim, and p21 (13–15). Our recent study showed that colon cancer cells contain a small fraction (~0.1%) of pre-existing FWB7 -mutant cells, which can be enriched upon treatment with the multi-kinase inhibitor regorafenib, leading to acquired drug resistance (29). It is possible that these cells can also escape from death induced by Hsp90 inhibitors and cause acquired resistance to these agents.…”

“…Mutant FBW7 and HA-ubiquitin expression constructs were previously described (24, 29). Transfection was performed using Lipofectamine 2000 (Invitrogen) according to the manufacturer’s instructions.…”