The proteostasis network in cancer cells is commonly challenged by dysregulated protein synthesis, protein imbalances caused by aneuploidy, and overexpression of oncogenes. Energy and nutrients can be severely limited due to inadequate blood supply. We hypothesize that in order to survive and thrive under these conditions, many cancer cells adapt their proteostasis network and become uniquely dependent on it - an example of non-oncogene addiction. Individual nodes of the proteostasis network, such as Hsp90 chaperones and the proteasome are currently exploited as drug targets in cancer - however, as with most targeted therapies, tumors often develop resistance.
We lack a comprehensive understanding of the proteostasis network that would enable us to characterize cancer-specific adaptations and nodes that could be targeted for combination therapies, preempting the development of drug resistance. Our functional genomics approach enables us to address these question and understand the rewiring of the proteostasis network in cancer cells. In collaborations with colleagues at UCSF and beyond, we investigate different types of cancer. Our major focus is on multiple myeloma, the second most common cancer of the blood, which is currently incurable.
Our research on cancer is funded by the National Cancer Institute / National Institutes of Health (Pathway to Independence Award) and Stand Up To Cancer / American Association for Cancer Research Innovative Research Grant.
- Acosta-Alvear D, Cho MY, Wild T, Buchholz TJ, Lerner AG, Simakova O, Hahn J, Korde N, Landgren O, Maric I, Choudhary C, Walter P, Weissman JS, Kampmann M (2015) Paradoxical resistance of multiple myeloma to proteasome inhibitors by decreased levels of 19S proteasomal subunits. eLife 10.7554/eLife.08153
- Kruth KA, Fang M, Shelton DN, Abu-Halawa O, Mahling R, Yang H, Weissman JS, Loh ML, Müschen M, Tasian SK, Bassik MC, Kampmann M, Pufall MA (2017) Suppression of B-cell development genes is key to glucocorticoid efficacy in treatment of acute lymphoblastic leukemia. Blood. 129(22):3000-3008.