VCP/p97 plays a critical role in protein homeostasis and cellular stress response pathways, several of which are important in cancer.
Cleave Therapeutics’ novel VCP/p97 inhibitors exploit molecular features that define cancer cell growth and metabolism. VCP/p97 plays a critical role in protein homeostasis processes such as endoplasmic reticulum associated degradation (ERAD) and chromatin associated degradation (CAD), as well as the DNA damage response (DDR). These key cellular stress pathways are known to represent sensitivities critical to cancer cell survival. Cellular stress provides an attractive means of targeting non-oncogene addiction as a way to combat tumor heterogeneity and emerging resistance to targeted therapies. Such an approach has the added benefit of broad applicability, not dependent on a single driver mutation and potential efficacy across cancer types.
Key results from various academic and government labs support the potential for VCP/p97 as a viable target in oncology, and recent results from large scale CRISPR screens performed by the Wellcome Sanger Institute identifying VCP/p97 as a pan-cancer core fitness gene in over 300 cell lines across 13 cancer types furthers this rationale.I Drugging these pathways provides a potential new therapeutic route for patients fighting cancer. VCP/p97 is an important cellular AAA ATPase that has a well described role as a master regulator in the Ubiquitin Proteasome System where it extracts misfolded proteins from membranes or protein complexes and chaperones them to the proteasome for degradation.II
VCP/p97 has also been shown to play a critical role in chromatin remodeling and the response to DNA damage.III-IV Emerging evidence suggests that cancer cells become over-dependent on protein homeostasis pathways for growth and survival, and therefore, inhibitors of VCP are expected to have meaningful anti-cancer activity.V Genetic knockdown of VCP leads to cell death in a number of solid tumor cell lines and compounds that inhibit VCP have been shown to drive cancer cell death in various pre-clinical models.VI-X
I. Behan, FM, Iorio, F, Picco, G, Gonçalves, E, Beaver CM, Migliardi, G, Santos, R, Rao, Y, Sassi, F, Pinnelli, M, Ansari, R, Harper, S, Jackson DA, McRae, R, Pooley, R, Wilkinson, P, van der Meer, D, Dow, D, Buser-Doepner, C, Bertotti, A, Trusolino, L, Stronach, EA, Saez-Rodrigues, J, Yusa, K, & Garnett, MJ (2019) Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens. Nature 568: 511-516
II. Meyer H, Bug M, Bremer S (2012) Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system. Nature Cell Biology 14: 117-123
III. Torrecilla et al (2017) The role of ubiquitin-dependent segregase p97 (VCP or Cdc48) in chromatin dynamics after DNA double strand breaks. Philos Trans Royal Soc Biol Sci
IV. Vaz et al (2013) Role of p97/VCP (Cdc48) in genome stability. Frontiers in Genetics
V. Cenci S, Oliva L, Cerruti F, Milan E, Bianchi G, Raule M, Mezghrani A, Pasqualetto E, Sitia R and Cascio P (2012) Protein synthesis modulates responsiveness of differentiating and malignant plasma cells to proteasome inhibitors. Journal of Leukocyte Biology 92: 921-931
VI. Magnaghi P, D’Alessio R, Valsasina B, Avanzi N, Rizzi S, Asa D, Gasparri F, Cozzi L, Cucchi U, Orrenius C, Polucci P, Ballinari D, Perrera C, Leone A, Cervi G, Casale E, Xiao Y, Wong C, Anderson DJ, Galvani A, Donati D, O’Brien T, Jackson PK and Isacchi A (2013) Covalent and allosteric inhibitors of the ATPase VCP/p97 induce cancer cell death. Nature Chemical Biology 9: 548-556
VII. Djakovic SN, Anderson DJ, Kiss von Soly S, Le Moigne R, Rice J, Rolfe M, Soriano F, Valle E, Wang J, Wong S, Wustrow D, Yakes FM, Yao B, Zhou H (2013) Novel small molecule inhibitors of p97 disrupt cellular protein homeostasis and demonstrate anti-tumor activity in solid and hematological models. Poster presented at: Proceedings of the 2013 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; Boston, Massachusetts
VIII. Daniel J. Anderson, Ronan Le Moigne, Stevan Djakovic, Brajesh Kumar, Julie Rice, Steve Wong, Jinhai Wang, Bing Yao, Eduardo Valle, Szerenke Kiss von Soly, Antonett Madriaga, Ferdie Soriano, Mary-Kamala Menon, Zhi Yong Wu, Martin Kampmann, Yuwen Chen, Jonathan S. Weissman, Blake T. Aftab, F. Michael Yakes, Laura Shawver, Han-Jie Zhou, David Wustrow, and Mark Rolfe (2015) Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis. Cancer Cell 28: 653–665
IX. Han-Jie Zhou, Jinhai Wang, Bing Yao, Steve Wong, Stevan Djakovic, Brajesh Kumar, Julie Rice, Eduardo Valle, Ferdie Soriano, Mary-Kamala Menon, Antonett Madriaga, Szerenke Kiss von Soly, Abhinav Kumar, Francesco Parlati, F. Michael Yakes, Laura Shawver, Ronan Le Moigne, Daniel J. Anderson, Mark Rolfe, David Wustrow (2015) Discovery of a First-in-Class, Potent, Selective, and Orally Bioavailable Inhibitor of the p97 AAA ATPase (CB-5083). J. Med. Chem 58, 24: 9480-9497
X. Ronan Le Moigne, Blake T. Aftab, Stevan Djakovic, Eugen Dhimolea, Eduardo Valle, Megan Murnane, Emily M. King, Ferdie Soriano, Mary-Kamala Menon, Zhi Yong Wu, Stephen T. Wong, Grace J. Lee, Bing Yao, Arun P. Wiita, Christine Lam, Julie Rice, Jinhai Wang, Marta Chesi, P. Leif Bergsagel, Marianne Kraus, Christoph Driessen, Szerenke Kiss Von Soly, F. Michael Yakes, David Wustrow, Laura Shawver, Han-Jie Zhou, Thomas G. Martin III, Jeffrey L. Wolf, Constantine S. Mitsiades, Daniel J. Anderson and Mark Rolfe (2017) The p97 Inhibitor CB-5083 Is a Unique Disrupter of Protein Homeostasis in Models of Multiple Myeloma. Mol. Cancer. Ther. 16: 2375-2386