Decrypting the role of HSP90α and β isoforms to overcome resistance in BCR-ABL1+ leukemia

ABSTRACT: BCR-ABL1+ leukemia entity still is associated with poor prognosis and new therapies are urgently needed. Heat shock proteins of 90 kDa (HSP90) have been widely studied due to their chaperone function, implicated in stabilizing various oncoproteins, including BCR-ABL1 kinase. However, HSP90 inhibitors (HSP90i) have not entered routinely in clinics, primarily due to the associated resistance via heat shock response (HSR) induction and dose limiting toxicity. Accordingly to study complications coupled with HSP90i, with aim to develop a novel strategy for therapy-refractory BCR-ABL1+ leukemia, genetic knockout (KO) models of cytosolic HSP90α/β isoforms were generated. Notably, β-KO cells displayed augmented HSR, whereas, α-KO cells revealed higher abundance of BCR-ABL1-foci and related hyperactive downstream pro-survival signaling. Although there is a strong compensatory behavior reported among HSP90α and β isoforms in their chaperoning their client proteins, global multi-omics profiling of α- vs. β-KO cells revealed a distinctive phenotype of the regulated signaling networks. Whereas in vivo engraftment of BCR-ABL1+ cells was found significantly reduced upon α-KO, validated by the prolonged overall survival of the mice. Later to investigate the acquired resistance evoked upon pharmacological targeting of HSP90, resistant cells were generated by chronic exposure of distinct HSP90i. Strikingly, clinically advanced (HSP90i) PU-H71-resistant cells acquired amplification and a distinctive mutation (S164F) in the HSP90AA1 locus, with concomitant elevation of HSP90α and ALDH1A1 expression, via activating ribosomal protein S6 kinase. Moreover BCR-ABL1+ cells displayed hypersensitivity toward CDK7i upon α-KO or when applied in combination with HSP90i, noticeably due to elevated CDK7 and androgen receptor (AR) signaling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE208005 | GEO | 2022/07/19

REPOSITORIES: GEO