Resistance to HSP90 inhibition involving loss of MCL1 addiction

Abstract

Inhibition of the chaperone heat-shock protein 90 (HSP90) induces apoptosis, and it is a promising anti-cancer strategy. The mechanisms underpinning apoptosis activation following HSP90 inhibition and how they are modified during acquired drug resistance are unknown. We show for the first time that, to induce apoptosis, HSP90 inhibition requires the cooperation of multi BH3-only proteins (BID, BIK, PUMA) and the reciprocal suppression of the pro-survival BCL-2 family member MCL1, which occurs via inhibition of STAT5A. A subset of tumour cell lines exhibit dependence on MCL1 expression for survival and this dependence is also associated with tumour response to HSP90 inhibition. In the acquired resistance setting, MCL1 suppression in response to HSP90 inhibitors is maintained; however, a switch in MCL1 dependence occurs. This can be exploited by the BH3 peptidomimetic ABT737, through non-BCL-2-dependent synthetic lethality.

Inhibition of HSP90 by AUY922 Preferentially Kills Mutant KRAS Colon Cancer Cells by Activating Bim through ER Stress

“…In particular, p53-dependent induction of the BH3-only protein PUMA has been shown to be responsible for apoptosis of colon cancer cells induced by the HSP90 inhibitor 17-AAG (10). Moreover, the antiapoptotic Bcl-2 family proteins, Bcl-2, Mcl-1, and Bcl-XL, have all been reported to protect cells against HSP90 inhibitioninduced apoptosis (9,(11)(12)(13).…”

“…This is frequently mediated by activation of the mitochondrial apoptotic pathway, which is regulated by the balance between proapoptotic and antiapoptotic Bcl-2 family proteins (8). Of note, multiple Bcl-2 family proteins are responsive to inhibition of HSP90 in a cell-type and context-dependent manner (9)(10)(11)(12). In particular, p53-dependent induction of the BH3-only protein PUMA has been shown to be responsible for apoptosis of colon cancer cells induced by the HSP90 inhibitor 17-AAG (10).…”

Circumventing hsp90 inhibitors via apoptosis block

“…We show that while de novo, intrinsically resistant cells fail to downregulate MCL1 and are not addicted to MCL1, clones with acquired resistance lose their addiction to MCL1 [6]. These findings therefore suggest that a possible correlation with 1q21 amplification which could be predictive for HSP90 inhibitors granting additional studies.…”

“…Intrinsic resistant cells fail to downregulate MCL1 as the result of a lack of STAT5A dephosphorylation, while conversely, and perhaps surprisingly, cells selected for resistance to HSP90 inhibition, MCL1 repression is conserved (Figure 1), along with other signalling perturbations consistent with on target HSP90 inhibition eg. MAPK and PI3K/AKT/mTOR pathways [6]. …”

“…This reversion to a sensitive phenotype is effected through BID and PUMA, while BIK becomes redundant (Figure 1). Genome-wide interrogation of CNVs in resistant cells reveals a substantial increase in the mutational burden, but absence of any specific CNVs in either BCL-xL or BCL-w [6]. …”