Dual targeting of BCL2 and MCL1 rescues myeloma cells resistant to BCL2 and MCL1 inhibitors associated with the formation of BAX/BAK hetero-complexes

Abstract

Multiple myeloma is a plasma cell malignancy that escapes from apoptosis by heterogeneously over-expressing antiapoptotic BCL2 proteins. Myeloma cells with a t(11;14) translocation present a particular vulnerability to BCL2 inhibition while a majority of myeloma cells relies on MCL1 for survival. The present study aimed to determine whether the combination of BCL2 and MCL1 inhibitors at low doses could be of benefit for myeloma cells beyond the single selective inhibition of BCL2 or MCL1. We identified that half of patients were not efficiently targeted neither by BCL2 inhibitor nor MCL1 inhibitor. Seventy percent of these myeloma samples, either from patients at diagnosis or relapse, presented a marked increase of apoptosis upon low dose combination of both inhibitors. Interestingly, primary cells from a patient in progression under venetoclax treatment were not sensitive ex vivo to neither venetoclax nor to MCL1 inhibitor, whereas the combination of both efficiently induced cell death. This finding suggests that the combination could overcome venetoclax resistance. The efficacy of the combination was also confirmed in U266 xenograft model resistant to BCL2 and MCL1 inhibitors. Mechanistically, we demonstrated that the combination of both inhibitors favors apoptosis in a BAX/BAK dependent manner. We showed that activated BAX was readily increased upon the inhibitor combination leading to the formation of BAK/BAX hetero-complexes. We found that BCLXL remains a major resistant factor of cell death induced by this combination. The present study supports a rational for the clinical use of venetoclax/S63845 combination in myeloma patients with the potential to elicit significant clinical activity when both single inhibitors would not be effective but also to overcome developed in vivo venetoclax resistance.

MCL-1 inhibitors, fast-lane development of a new class of anti-cancer agents

“…Accordingly, BH3 profiling and interaction analyses of pro- and anti-apoptotic BCL-2 family members (e.g., MCL-1/BCL-xL/BCL-2 binding to Bim) predict the efficacy of BH3-mimetics in MM [ 6 , 91 ]. Conflicting results exist in relation to the impact of amplification of 1q21 and MCL-1 inhibitor sensitivity [ 92 , 93 ].…”

Simultaneously Inhibiting BCL2 and MCL1 Is a Therapeutic Option for Patients with Advanced Melanoma

“…In comparison, the combination of ABT-199 plus an MCL1 inhibitor has been tested in pre-clinical mouse studies and is considered safe even when administered at higher concentrations than what we demonstrate in this current study (S63845: 25 mg/kg twice weekly; ABT199: 50 mg/kg 2-3 times per week). For instance, Seiller et al [52] used ABT-199 (100 mg/kg; 5 days/week) along with S63845 (25 mg/kg; every 6 days) for 19 days without significant weight loss in NOD scid gamma (NSG) mice. Prukova et al [32] safely administered S63845 (25 mg/kg) and ABT-199 (50 mg/kg) simultaneously in a mouse model of AML for five days.…”

“…The tumor samples were collected at the end of the experiment for further studies. The doses used here were chosen based on a thorough literature search and our pilot experiments, and these doses were safe in similar doses for other cancers [32,[50][51][52].…”

BCL2 Family Inhibitors in the Biology and Treatment of Multiple Myeloma

“… 76 However, a second study of 27 patient samples did not report any difference in sensitivity between the two groups. 77 …”

“…The effectiveness of both S63485 and AMG176 was inversely correlated with BCL2 and BCLXL expression in myeloma, AML, and CML. 68 , 69 , 76 , 77 Furthermore, the BIM released from MCL1 by MCL1 inhibitors has been observed to shift to BCL2 or BCLXL. 78 , 79 Given the potential for other BCL2 proteins to contribute to MCL1 inhibitor resistance, a number of studies have examined combinations of different BCL2 family inhibitors.…”