Cambridge, Massachusetts, United States
There is a plethora of tumor-specific genomic alterations that directly or indirectly involve transcription factors (TFs), highlighting their potential as anti-cancer drug targets. NFE2L2 (aka NRF2) is a TF that plays a central role in the protection of cells from oxidative and electrophilic stress. NRF2 enables adaptation to oxidants and electrophiles by inducing the transcription of several cytoprotective genes, including those involved in the elimination of ROS (reactive oxygen species), glutathione synthesis, xenobiotic metabolism, and drug transport. Under normal, unstressed conditions, the levels of NRF2 are kept low in the cell by KEAP1, an adaptor for a CUL3-based E3 ligase complex, which facilitates NRF2 ubiquitination and degradation. Upon stress, reactive cysteine thiol residues in KEAP1 are modified, thereby inhibiting KEAP1 and preventing NRF2 turnover, leading to NRF2 nuclear accumulation and activation of its target genes. NRF2, and its negative regulators KEAP1 and CUL3, are significantly mutated in several cancers, including lung (squamous cell carcinoma and adenocarcinoma), head and neck, and bladder. In these cancers, NRF2 is constitutively active, and cell line models that carry a mutation in the NRF2 pathway are dependent on NRF2 for their survival. My group is interested in gaining a better understanding of NRF2 as a genetic target in cancer. To this end, we are using functional genomic screens and proteomic approaches to identify key regulators of the NRF2 pathway and NRF2 itself that are critical for its transcriptional activity.
Inhibiting Tankyrases sensitizes KRAS-mutant cancer cells to MEK inhibitors via FGFR2 feedback signaling.
Schoumacher M, Hurov KE, Lehár J, Yan-Neale Y, Mishina Y, Sonkin D, Korn JM, Flemming D, Jones MD, Antonakos B, Cooke VG, Steiger J, Ledell J, Stump MD, Sellers WR, Danial NN, Shao W.
Cancer Research 2014 June 15; 74(12):3294-305.
Integrative radiogenomic profiling of squamous cell lung cancer.
Abazeed ME, Adams DJ, Hurov KE, Tamayo P, Creighton CJ, Sonkin D, Giacomelli AO, Du C, Fries DF, Wong KK, Mesirov JP, Loeffler JS, Schreiber SL, Hammerman PS, Meyerson M.
Cancer Res. 2013 Oct 15; 73(20):6289-98.
A genetic screen identifies the Triple T complex required for DNA damage signaling and ATM and ATR stability.
Hurov KE, Cotta-Ramusino C, Elledge SJ.
Genes Dev. 2010 Sept 1; 24(17):1939-50.
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