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.
Highlights
Heat shock protein 70 (Hsp70) is an important molecular chaperone that regulates oncoprotein stability and tumorigenesis
We propose that targeting DNAJA1 in cancer may offer an attractive alternative to the toxicity induced by full Hsp90/Hsp[70] inhibition
Hsp[70] in cancer have been thoroughly studied, much less is known of the role that regulatory co-chaperone proteins such as DNAJA1 play in tumorigenesis
Summary
Heat shock protein 70 (Hsp70) is an important molecular chaperone that regulates oncoprotein stability and tumorigenesis. Rather than targeting Hsp[70] itself, here we have examined the feasibility of inhibiting the Hsp[70] co-chaperone DNAJA1 as a novel anticancer strategy. 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 elevated levels of Hsp[90] and Hsp[70] chaperones in cancer and their role in fostering multiple oncogenic pathways has made these proteins attractive drug targets with numerous anti-chaperone compounds having been developed so far[3]. We propose that targeting DNAJA1 in cancer may offer an attractive alternative to the toxicity induced by full Hsp90/Hsp[70] inhibition
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