Targeting CDC37: an alternative, kinase-directed strategy for disruption of oncogenic chaperoning.
Interest in HSP90 inhibitors has grown rapidly in the last decade. The heightened dependence of malignant cells on molecular chaperones to maintain multiple oncogenic signalling pathways gives HSP90 broad anticancer appeal. New HSP90-directed agents are continually emerging, several of which are under clinical evaluation. In parallel, dissection of the functional mechanism of the chaperone system has emphasised the importance of cochaperones that regulate HSP90. As we begin to fully elucidate the roles of these HSP90 accessory proteins, it is becoming increasingly clear that they too have potential as additional routes to disrupt chaperone activity. CDC37, a predominantly kinase client-associated cochaperone that promotes malignant transformation, has particular promise. Recently, we demonstrated that, similar to HSP90 inhibitors, siRNA-mediated CDC37 silencing caused the proteasomal degradation of kinase client proteins and inhibited the proliferation of cancer cells. Importantly, depleting CDC37 does not induce the unwanted, antiapoptotic heat shock response that is characteristic of pharmacologic HSP90 inhibition. Furthermore, CDC37 silencing sensitises cancer cells to HSP90 inhibitors by potentiating kinase client depletion and the induction of apoptosis, suggesting that simultaneously modulating HSP90 and CDC37 could be beneficial. Here we discuss the therapeutic possibilities of targeting CDC37 for cancer treatment in light of recent significant findings.
Smith
Jennifer R
JR
Signal Transduction and Molecular Pharmacology Team, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey, UK.
Workman
Paul
P
D000818:Animals; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D018833:Chaperonins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011487:Protein Conformation; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D034741:RNA, Small Interfering; D018833:Chaperonins