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. Therefore, rather than targeting Hsp70 itself, here we have examined the feasibility of inhibiting the co-chaperone HDJ2, a member of the J domain protein family, as a novel anticancer strategy. We found HDJ2 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 HDJ2 in cancer. 41 compounds showed strong synergy with HDJ2 loss, whereas 18 dramatically lost potency. Several of these hits were validated using a HDJ2 inhibitor (116-9e) in castration-resistant prostate cancer cell (CRPC) and spheroid models. Taken together, these results confirmed that HDJ2 is a hub for anticancer drug resistance and that HDJ2 inhibition may be a potent strategy to sensitize cancer cells to current and future therapeutics.
Graphical Abstract HDJ2 knockout or inhibition via small molecule impacts cellular resistance to anticancer therapeutics.
Footnotes
The authors declare no potential conflicts of interest.