Chemogenomic screening Identifies the Hsp70 Co-chaperone HDJ2 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. 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.\n\nGraphical AbstractHDJ2 knockout or inhibition via small molecule impacts cellular resistance to anticancer therapeutics.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC=\"FIGDIR/small/818427v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (86K):\norg.highwire.dtl.DTLVardef@cc1f42org.highwire.dtl.DTLVardef@1184229org.highwire.dtl.DTLVardef@19f9b8aorg.highwire.dtl.DTLVardef@19c9037_HPS_FORMAT_FIGEXP M_FIG C_FIG