MCL-1-independent mechanisms of synergy between dual PI3K/mTOR and BCL-2 inhibition in diffuse large B cell lymphoma

Abstract

The PI3K/AKT/mTOR axis promotes survival and is a frequently mutated pathway in cancer. Yet, inhibitors targeting this pathway are insufficient to induce cancer cell death as single agents in some contexts, including diffuse large B cell lymphoma (DLBCL). In these situations, combinations with inhibitors targeting BCL-2 survival proteins (ABT-199 and ABT-263) may hold potential. Indeed, studies have demonstrated marked synergy in contexts where PI3K/mTOR inhibitors suppress expression of the pro-survival protein, MCL-1. In this study, we use BH3 profiling to confirm that BCL-2 and BCL-XL support survival following PI3K pathway inhibition, and that the dual PI3K/mTOR inhibitor BEZ235 strongly synergizes with BCL-2 antagonists in DLBCL. However, we identify an alternative mechanism of synergy between PI3K/mTOR and BCL-2 inhibitors, independent of MCL-1 down-regulation. Instead, we show that suppression of AKT activation by BEZ235 can induce the mitochondrial accumulation of pro-apoptotic BAD and BIM, and that expression of a constitutively active form of AKT prevents sensitization to BCL-2 antagonism. Thus, our work identifies an additional mechanism of synergy between PI3K pathway inhibitors and BCL-2 antagonists that strengthens the rationale for testing this combination in DLBCL.

Targeting mTOR for the treatment of B cell malignancies

“…ABT‐199 is a selective inhibitor of BCL‐2 and has elicited substantial clinical responses in patients with CLL as a single agent , leading to its designation as a breakthrough therapy for CLL patients with a 17p deletion (p53). Importantly, we and others have recently reported that ABT‐199 synergizes with mTOR inhibition comparably with dual BCL‐2/BCL‐X L inhibitors , suggesting that the rationale established using first generation BCL‐2 antagonists will hold true for ABT‐199. However, a key concern is whether the addition of TOR‐KIs to BCL‐2 antagonists will enhance their toxicity towards non‐cancer cells.…”

“…However, in both studies, apoptosis was only observed at doses of TOR‐KI that greatly exceed what was needed to suppress fully mTOR kinase activity as measured by western blot . At lower doses that still fully suppress mTOR activity, our laboratory has found that both AZD8055 and MLN0128 maintain a primarily cytostatic response profile (that is greater than rapalogs) . Notably, low doses of PP242 were sufficient to kill murine bone marrow cells immortalized by p190‐BCR‐ABL , suggesting that fully transformed B‐ALL cells with additional oncogenic lesions may respond differently to mTOR inhibition.…”

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax

“…In these cases, adding a CDK9 inhibitor (alvocidib/flavopiridol) or a direct inhibitor of MCL-1 (A-1210477) to venetoclax leads to synergistic cell killing (65). Additional synergies may also exist with other pathways known to promote tumor cell survival, as has been reported using the dual PI3K/mTOR (mammalian target of rapamycin) inhibitor BEZ235 and venetoclax (66). …”

Bruton tyrosine kinase inhibitor ONO/GS-4059: from bench to bedside

“…Novel targeted agents have led to revolutions of lymphoma treatment [22–31]. Since BTK plays a critical role in B cell development and lymphomagenesis, BTK inhibitors have been in active clinical development [32–36].…”