- Joint Appointment in Oncology
Departments / Divisions
- Oncology - Cancer Invasion and Metastasis
Utthara Nayar, Ph.D.
Targeted Therapy Resistance in Metastatic Breast Cancer ...read more
The primary reason for breast cancer mortality is the development of resistance, through largely unknown mechanisms, to targeted anti-estrogen therapies in ER+ MBC. Dr. Nayar recently identified acquired activating mutations in human epidermal growth factor receptor 2 (HER2), which activates the MAPK pathway, in patients with resistance, and demonstrated that these directly conferred resistance to anti-ER agents. Since MAPK-activation represents an emerging class of resistance whose incidence is rising in the clinic, a deeper understanding of the biology and therapeutic vulnerabilities of tumors bearing such mutations or related genetic alterations in the MAPK pathway is required. The scientific objective of Dr. Nayar’s research program is to study tumor cell-intrinsic signaling, tumor evolution, and the tumor (+immune) microenvironment of resistant breast cancer, through cell, molecular, and large-scale genomic/epigenomic approaches, using MAPK-activated endocrine-resistant ER+ breast cancer as a model. Additionally, Dr. Nayar has spearheaded cancer variant-to-function screens (deep mutational scanning of oncogenic kinases), with the aim of identifying general rules to infer function/activity/resistance phenotype from cancer variant.
The Nayar laboratory is focused on the biology of therapeutic resistance in breast cancer. Dr. Nayar recently identified a subset of estrogen receptor-positive (ER+) metastatic breast cancer that is resistant to ER-targeted therapy by acquiring mutations in the growth factor molecule HER2. The laboratory aims to understand the mechanism(s) by which a tumor becomes resistant to targeted therapy, employing this subset of breast cancer as a model.
Lab Website: Nayar Lab
Breast cancer, cancer biology, cell biology, functional genomics
Mao, P, Cohen, O, Kowalski, KJ, Kusiel, JG, Buendia-Buendia, JE, Cuoco, MS, Exman, P, Wander, SA, Waks, AG, Nayar, U, Chung, J, Freeman, S, Rozenblatt-Rosen, O, Miller, VA, Piccioni, F, Root, DE, Regev, A, Winer, EP, Lin, NU, Wagle, N. Acquired FGFR and FGF alterations confer resistance to estrogen receptor (ER) targeted therapy in ER+ metastatic breast cancer. Clinical Cancer Research. 2020 Nov 15;26(22):5974-5989
Wander, SA, Cohen, O, Gong, X, Johnson, GN, Buendia-Buendia, JE, Lloyd, MR, Kim, D, Luo, F, Mao, P, Helvie, K, Kowalski, KJ, Nayar, U, Waks, AG, Parsons, SH, Martinez, R, Litchfield, LM, Ye, XS, Yu, C, Jansen,VM, Stille, JR, Smith, PS, Oakley, GJ, Chu, QS, Batist, G, Hughes, ME, Kremer, JD, Garraway, LA, Winer, EP, Tolaney, SM, Lin, NU, Buchanan, SG, Wagle, N. The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors in patients with hormone receptor-positive metastatic breast cancer. Cancer Discovery. 2020 Aug;10(8):1174-1193
Persky, NS, Hernandez, D, Do Carmo, M, Brenan, L, Cohen, O, Kitajima, S, Nayar, U, Walker, A, Pantel, S, Lee, Y, Cordova, J, Sathappa, M, Zhu, C, Hayes, T, Pancholi, P, Ram, P, Mikkelsen, TS, Barbie, DA, Yang, X, Haq, R, Piccioni, F, Root, D, Johannessen, CM. Defining the landscape of ATP-competitive inhibitor resistance residues in protein kinases. Nature Structural and Molecular Biology. 2020 Jan 10; 27: 92-104
Nayar, U, Cohen, O, Kapstad, CJ, Waks, A, Wander, S, Marini, L, Helvie, K, Oliver, N, Persky, N, Painter, C, Freeman, S, Lin, NU, Winer, EP, Ma, CX, Wagle, N. Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to ER-directed therapies. Nature Genetics. 2019 Feb 1; 51(2): 207-216
Nayar, U, Sadek, J, Reichel, J, Hernandez-Hopkins, D, Akar, G, Barelli, PJ, Sahai, MA, Zhou, H, Totonchy, J, Jayabalan, D, Niesvizky, R, Guasparri, I, Hassane, D, Liu, Y, Sei, S, Shoemaker, R, Warren, DW, Elemento, O, Kaye, KM, Cesarman, E. Identification of a nucleoside analog active against adenosine kinase-expressing plasma cell malignancies. Journal of Clinical Investigation. 2017 Jun 1; 127(6): 2066-2080. (PMID: 28504647)
Novel nucleoside analogs and use thereof in therapeutic treatment.
Patent # PCT/US2017/027590 |
This invention describes potential use of a family of nucleoside analogs in malignancies expressing adenosine kinase (ADK), in particular plasma cell tumors such as KSHV+ primary effusion lymphoma (PEL), and multiple myeloma (MM). The family of compounds described is under further preclinical testing for selected incurable plasma cell malignancies, and may move on to clinical trials pending safety and efficacy profiling. I characterized the compound from a screen, determined the mechanism of activation (phosphorylation by ADK) using genomics and in vitro studies- which led to the identification of ADK as a biomarker for response- and performed preclinical studies to demonstrate potent efficacy in mouse models of PEL.
Evolving mutations in metastatic breast cancer, BreastCancer.org (2018)
Highlighted as one of four stories of interest at Press Preview before AACR Annual Meeting 2018, American Association for Cancer Research (March 15, 2018)
Utthara Nayar is targeting cancer drug resistance, Broad Institute of MIT and Harvard (March 19, 2018)
Utthara Nayar Joins BMB Faculty, Johns Hopkins Bloomberg School of Public Health (2021)