My lab focuses on understanding the regulation of growth factor signal transduction pathways that are aberrantly activated in cancers, with a focus on those implicated in breast cancer pathogenesis.
One major effort in the lab is examining the regulation of the PI3K pathway, including the identification and characterization of feedback and cross-talk pathways among the different subtypes of breast cancer that feature PI3K/AKT/mTOR activation, the determination of the biological significance of the negative feedback in tumor phenotypes, preclinical and early-phase clinical development of pharmacologic strategies to overcome feedback-mediated resistance to PI3K/AKT/mTOR inhibitors, and analysis of human tumor samples to more comprehensively understand therapeutic resistance to targeted therapy in breast cancer.
A second major effort is geared toward examining the significance of mutations in the estrogen receptor in cancer, including the identification of different means of hormone independent ER activation in cancer, determination of the consequences of specific mutations on ER activation and action, and development of inhibitors that potently antagonize both wild type and mutant forms of ER.
Chandarlapaty, S., Sawai, A., Scaltriti, M., Rodrik-Outmezguine, V., Grbovic-Huezo, O., Serra, V., Majumder, P.K., Baselga, J., Rosen, N. (2011) AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell, Jan 18;19(1):58-71.
Carver B, Chapinski C, Wongvipat J, Hieronymous H, Chen Y, Chandarlapaty S, Arora V, Le C, Koutcher J, Scher H, Scardino PT, Rosen N, Sawyers CL. (2011) Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell, May 17;19(5): 575-586.
Rodrik-Outmezguine R, Chandarlapaty S, Pagano NC, Poulikakos PI, Scaltriti M, Moskatel E, Baselga J, Guichard S, Rosen N. (2011) mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling. Cancer Discov. 2011 Jun 17;1(3):248-259.
Toy W, Shen Y, Won H, Green B, Sakr RA, Will M, Li Z, Gala K, Fanning S, King TA, Hudis C, Chen D, Taran T, Hortobagyi G, Greene G, Berger M, Baselga J, Chandarlapaty S. (2013) ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet. Dec;45(12):1439-45.
Will M, Qin AC, Toy W, Yao Z, Rodrik-Outmezguine V, Schneider C, Huang X, Monian P, Jiang X, de Stanchina E, Baselga J, Liu N, Chandarlapaty S*, Rosen N.* (2014) Rapid induction of apoptosis by PI3K inhibitors is dependent upon their transient inhibition of RAS-ERK signaling. Cancer Discov. Mar;4(3):334-47.
Clinical Investigator Award, Damon Runyon Cancer Research Foundation (2012)
Young Investigator Award, American Society of Clinical Oncology (2007)
Fellow in Biomedical Research, The Dana Foundation (2006)