Mcl-1 inhibition overcomes intrinsic and acquired regorafenib resistance in colorectal cancer.
Intrinsic and acquired resistance to targeted therapies is a significant clinical problem in cancer. We previously showed that resistance to regorafenib, a multi-kinase inhibitor for treating colorectal cancer (CRC) patients, can be caused by mutations in the tumor suppressor <i>FBW7</i>, which block degradation of the pro-survival Bcl-2 family protein Mcl-1. We tested if Mcl-1 inhibition can be used to develop a precision combination therapy for overcoming regorafenib resistance.
Small-molecule Mcl-1 inhibitors were tested on CRC cells with knock-in (KI) of a non-degradable Mcl-1. Effects of Mcl-1 inhibitors on regorafenib sensitivity were determined in <i>FBW7</i>-mutant and -wild-type (WT) CRC cells and tumors, and in those with acquired regorafenib resistance due to enriched <i>FBW7</i> mutations. Furthermore, translational potential was explored by establishing and analyzing <i>FBW7</i>-mutant and -WT patient-derived organoid (PDO) and xenograft (PDX) tumor models.
We found that highly potent and specific Mcl-1 inhibitors such as S63845 overcame regorafenib resistance by restoring apoptosis in multiple regorafenib-resistant CRC models. Mcl-1 inhibition re-sensitized CRC tumors with intrinsic and acquired regorafenib resistance <i>in vitro</i> and <i>in vivo,</i> including those with <i>FBW7</i> mutations. Importantly, Mcl-1 inhibition also sensitized <i>FBW7</i>-mutant PDO and PDX models to regorafenib. In contrast, Mcl-1 inhibition had no effect in <i>FBW7</i>-WT CRCs.
Our results demonstrate that Mcl-1 inhibitors can overcome intrinsic and acquired regorafenib resistance in CRCs by restoring apoptotic response. <i>FBW7</i> mutations might be a potential biomarker predicting for response to the regorafenib/Mcl-1 inhibitor combination.
- Kuang C
- Pei H
- Schoen RE
- Shen L
- Song X
- Tong J
- Yu J
- Zeng S
- Zhang L