mTOR Inhibition Specifically Sensitizes Colorectal Cancers with KRAS or BRAF Mutations to BCL-2/BCL-XL Inhibition by Suppressing MCL-1

Abstract

Colorectal cancers (CRCs) harboring KRAS or BRAF mutations are refractory to current targeted therapies. Using data from a high-throughput drug screen, we have developed a novel therapeutic strategy that combines targeting of the apoptotic machinery using the BCL-2 family inhibitor ABT-263 (navitoclax) in combination with a TORC1/2 inhibitor, AZD8055. This combination leads to efficient apoptosis specifically in KRAS mutant (MT) and BRAF MT but not wild-type (WT) CRC cells. This specific susceptibility results from TORC1/2 inhibition leading to suppression of MCL-1 expression in mutant, but not WT CRCs, leading to abrogation of BIM/MCL-1 complexes. This combination strategy leads to tumor regressions in both KRAS MT colorectal cancer xenograft and genetically-engineered mouse models of CRC, but not in the corresponding KRAS WT CRC models. These data suggest that the combination of BCL-2/XL inhibitors with TORC1/2 inhibitors constitutes a promising targeted therapy strategy to treat these recalcitrant cancers.

mTOR Complex 2 Stabilizes Mcl-1 Protein by Suppressing Its Glycogen Synthase Kinase 3-Dependent and SCF-FBXW7-Mediated Degradation

“…2F and 3A). These findings are similar to the previous report that ADZ8055-induced Mcl-1 reduction is not associated with mRNA modulation (28). Thus, it is clear that TORKinibs do not downregulate Mcl-1 at the mRNA level.…”

“…Hence, downregulation of Mcl-1 by TORKinibs may not be sufficient to initiate apoptosis but may lower the threshold at which cancer cells undergo apoptosis, meaning that TORKinibs may sensitize cancer cells to certain cancer therapy-induced apoptosis. Indeed, two recent studies have shown that TORKinibs such as AZD8055 enhance the effects of the Bcl-2 family inhibitors AB263 and ABT737 on the induction of apoptosis and on their cancer therapeutic efficacies (27,28). In our study, we also show that the chemotherapeutic drug CDDP, in combination with either INK128 or AZD8055, exerts enhanced effects on decreasing Mcl-1 levels, inducing apoptosis, and suppressing the growth of cancer cells both in vitro and in vivo ( Fig.…”

“…1). During the course of our studies of Mcl-1 downregulation by TORKinibs, two other groups reported that AZD8055 decreased Mcl-1 levels in rhabdomyosarcoma and colorectal cancer cells, although the underlying mechanisms were not defined (27,28). Hence, it is clear that TORKinibs decrease Mcl-1 levels in cancer cells.…”

PI3K and Bcl-2 Inhibition Primes Glioblastoma Cells to Apoptosis through Downregulation of Mcl-1 and Phospho-BAD

“…This class of molecules is more effective in tumors with high levels of bcl-2/bcl-xL. ABT-263 is currently under investigation in various malignancies, either as a single drug compound, or in combination with other antitumor reagents (8,9) and has already reached clinical trials (10). Specifically, preclinical studies, involving ABT-263, have shown that it has activity against small cell lung cancer (SCLC) as well as acute lymphoblastic leukemia (7).…”

Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer

“…These compounds bind to and inhibit antiapoptotic BCL-2 family members, the molecular sentinels of apoptosis. ABT-263 (5) is a BH3 mimetic that directly binds BCL-2 and BCL-XL, which blocks their binding to BIM and thereby enables BIMmediated induction of apoptosis (6)(7)(8). However, ABT-263 does not bind the prosurvival BCL-2 family member myeloid cell leukemia 1 (MCL-1), and high levels of MCL-1 are associated with resistance to BH3 mimetics such as ABT-263 in both the laboratory and the clinic (9)(10)(11)(12)(13)(14)(15)(16)(17).…”