Co-Mentor: Darrin Stuart, PhD
Oncology
Cambridge, Massachusetts, United States
The MAPK pathway is highly mutated in human cancers and although inhibitors have been developed to target multiple nodes, the therapeutic efficacy of these agents is still plagued by both intrinsic and acquired resistance. Our group seeks to gain a deeper understanding of MAPK pathway signaling in order to find novel ways of targeting these cancers. Our research focus covers three main aspects of the RAS-RAF-MEK-ERK signaling cascade: i) understanding basic pathway biology, ii) drug discovery, and iii) understanding resistance to pharmacological inhibition.
We are interested in examining multiple levels of regulation of the MAPK pathway including the mechanisms of activation, ERK-mediated negative feedback loops, and the regulation of signaling through the DUSP family of phosphatases. We are also investigating synthetic lethality in MAPK-mutated cancers to potentially find novel ways of inhibiting tumor cell growth. For example, a large pooled shRNA screen indicates that BRAFV600E melanoma cell lines are preferentially dependent on ERK2, rather than ERK1. These data confirm previous work in our group that further demonstrated this dependence pharmacologically, using an ATP-competitive inhibitor and drug resistant mutants of each isoform. These results are somewhat surprising given the sequence homology between ERK1 and ERK2 and the strong evidence of functional redundancy in the literature. We therefore are seeking a deeper understanding of the intricacies of ERK1 vs ERK2 signaling in cancer, which could lead to improved therapeutic approaches.
Selected Publications
Selected Publications for Alyson Freeman, PhD
The importance of Raf dimerization in cell signaling.
Freeman AK, Ritt DA, Morrison DK.
Small GTPases. 2013 Jul-Sep;4(3):180-5.
Effects of Raf dimerization and its inhibition on normal and disease-associated Raf signaling.
Freeman AK, Ritt DA, Morrison DK.
Mol Cell. 2013 Feb 21;49(4):751-8.
Complexity in KSR function revealed by Raf inhibitor and KSR structure studies.
McKay MM, Freeman AK, Morrison DK.
Small GTPases. 2011 Sep;2(5):276-281. Epub 2011 Sep 1.
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Selected Publications for Darrin Stuart, PhD
Vemurafenib cooperates with HPV to promote initiation of cutaneous tumors.
Holderfield M, Lorenzana E, Weisburd B, Lomovasky L, Boussemart L, Lacroix L, Tomasic G, Favre M, Vagner S, Robert C, Ghoddusi M, Daniel D, Pryer N, McCormick F, Stuart D.
Cancer Res. 2014 Apr 15;74(8):2238-45.
Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance.
Das Thakur M, Salangsang F, Landman AS, Sellers WR, Pryer NK, Levesque MP, Dummer R, McMahon M, Stuart DD.
Nature. 2013 Feb 14;494(7436):251-5.
RAF inhibitors activate the MAPK pathway by relieving inhibitory autophosphorylation.
Holderfield M, Merritt H, Chan J, Wallroth M, Tandeske L, Zhai H, Tellew J, Hardy S, Hekmat-Nejad M, Stuart DD, McCormick F, Nagel TE.
Cancer Cell. 2013 May 13;23(5):594-602.
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