Co-targeting HSP90 alpha and CDK7 overcomes resistance against HSP90 inhibitors in BCR-ABL1+leukemia cells

HSP90 has emerged as an appealing anti-cancer target. However, HSP90 inhibitors (HSP90i) are characterized by limited clinical utility, primarily due to the resistance acquisition via heat shock response (HSR) induction. Understanding the roles of abundantly expressed cytosolic HSP90 isoforms (alpha and beta) in sustaining malignant cells' growth and the mechanisms of resistance to HSP90i is crucial for exploiting their clinical potential. Utilizing multi-omics approaches, we identified that ablation of the HSP90 beta isoform induces the overexpression of HSP90 alpha and extracellular-secreted HSP90 alpha (eHSP90 alpha). Notably, we found that the absence of HSP90 alpha causes downregulation of PTPRC (or CD45) expression and restricts in vivo growth of BCR-ABL1+ leukemia cells. Subsequently, chronic long-term exposure to the clinically advanced HSP90i PU-H71 (Zelavespib) led to copy number gain and mutation (p.S164F) of the HSP90AA1 gene, and HSP90 alpha overexpression. In contrast, acquired resistance toward other tested HSP90i (Tanespimycin and Coumermycin A1) was attained by MDR1 efflux pump overexpression. Remarkably, combined CDK7 and HSP90 inhibition display synergistic activity against therapy-resistant BCR-ABL1+ patient leukemia cells via blocking pro-survival HSR and HSP90 alpha overexpression, providing a novel strategy to avoid the emergence of resistance against treatment with HSP90i alone.

Automated summary

HSP90 has emerged as an appealing anti-cancer target, but its inhibitors are limited by the development of resistance. This study identified that the loss of HSP90 beta isoform leads to overexpression of HSP90 alpha and extracellular-secreted HSP90 alpha. Additionally, the absence of HSP90 alpha restricts the growth of leukemia cells.