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.
Highlights
Targeting the molecular chaperone heat-shock protein 90 (HSP90)is an attractive therapeutic strategy for treating cancer
To determine whether HSP90 inhibition modifies the expression of pro-survival BCL-2 family proteins to promote apoptosis, we examined the expression of BCL-2, BCL-xL, BCL-w, MCL1 and BCL2A1 pre- and post-HSP90 inhibition, and identified MCL1 downregulation as the sole modification across this pro-survival protein repertoire (Figure 2a, Supplementary Figure S3A)
We have shown that apoptosis induced by inhibition of HSP90 involves the mitochondrial pathway and is activated by the reciprocal regulation of specific pro-apoptotic and anti-apoptotic BCL-2 family proteins
Summary
Targeting the molecular chaperone heat-shock protein 90 (HSP90). Is an attractive therapeutic strategy for treating cancer. HSP90 is essential for the maturation of client proteins, and its inhibition leads to client misfolding, ubiquitination and proteasomal degradation.[1] HSP90 inhibition is pleiotropic in its targeting, effectively inhibiting cancer networks.[2,3,4,5] The mechanisms underpinning resistance are poorly understood. HSP90 inhibition efficiently induces cancer cell apoptosis and may be selective to chaperone-dependent oncogenic drivers such as EML4-ALK.[6] Different variants of the EML4-ALK fusion protein exhibit different stability and sensitivity to HSP90 inhibition[7] and our recent data suggest that specific EML4-ALK variants exhibit differential sensitivity to HSP90 inhibition-mediated ubiquitination and degradation, owing to their TAPE domain structure.[8]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
