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Chemogenomic screening identifies the Hsp70 co-chaperone DNAJA1 as a hub for anticancer drug resistance.


ABSTRACT: Heat shock protein 70 (Hsp70) is an important molecular chaperone that regulates oncoprotein stability and tumorigenesis. However, attempts to develop anti-chaperone drugs targeting molecules such as Hsp70 have been hampered by toxicity issues. Hsp70 is regulated by a suite of co-chaperone molecules that bring "clients" to the primary chaperone for efficient folding. Rather than targeting Hsp70 itself, here we have examined the feasibility of inhibiting the Hsp70 co-chaperone DNAJA1 as a novel anticancer strategy. We found DNAJA1 to be upregulated in a variety of cancers, suggesting a role in malignancy. To confirm this role, we screened the NIH Approved Oncology collection for chemical-genetic interactions with loss of DNAJA1 in cancer. 41 compounds showed strong synergy with DNAJA1 loss, whereas 18 dramatically lost potency. Several hits were validated using a DNAJA1 inhibitor (116-9e) in castration-resistant prostate cancer cell (CRPC) and spheroid models. Taken together, these results confirm that DNAJA1 is a hub for anticancer drug resistance and that DNAJA1 inhibition is a potent strategy to sensitize cancer cells to current and future therapeutics. The large change in drug efficacy linked to DNAJA1 suggests a personalized medicine approach where tumor DNAJA1 status may be used to optimize therapeutic strategy.

SUBMITTER: Nitika 

PROVIDER: S-EPMC7429498 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Chemogenomic screening identifies the Hsp70 co-chaperone DNAJA1 as a hub for anticancer drug resistance.

Nitika   Blackman Jacob S JS   Knighton Laura E LE   Takakuwa Jade E JE   Calderwood Stuart K SK   Truman Andrew W AW  

Scientific reports 20200814 1


Heat shock protein 70 (Hsp70) is an important molecular chaperone that regulates oncoprotein stability and tumorigenesis. However, attempts to develop anti-chaperone drugs targeting molecules such as Hsp70 have been hampered by toxicity issues. Hsp70 is regulated by a suite of co-chaperone molecules that bring "clients" to the primary chaperone for efficient folding. Rather than targeting Hsp70 itself, here we have examined the feasibility of inhibiting the Hsp70 co-chaperone DNAJA1 as a novel a  ...[more]

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