Cyril Benes, PhD

Network representation of genomic correlates shared by MEK1/2 and RAF inhibitors indentified by
linear regression using drug sensitivity data across hundreds of cancer cell lines.
Resistance to Cancer Therapies
Even for the most successful anticancer
therapies, drug resistance invariably emerges
and limits the impact on patient lives. The
molecular mechanisms underlying acquired
resistance to cancer therapeutics are not well
defined but are likely to be different for each
therapy and cancer. We are investigating how
drug combinations could overcome resistance,
and within this context, studying how changes
in intracellular signaling pathways affect drug
response.
We are tackling the problem of therapeutic
resistance using cell lines made resistant in the
laboratory or isolated from resistant tumors.
Previous results have shown that these cell line
models do recapitulate at least some of the
mechanisms of resistance at play in patients.
We interrogate combinations of a panel of
clinically relevant anticancer drugs as a way to
quickly identify candidate therapeutic strategies
and to jumpstart mechanistic studies that
will help characterize the molecular basis of
acquired resistance.
We are also approaching the problem
of resistance using a very different and
complementary approach. We systematically
identify genes that can cause resistance
to a given drug in a given context using a
transposon-based genetic screen. Transposons
are mobile genetic elements that can insert
into a host genome—in our case, the genome
of cancer cells. We use an engineered version
of a transposon so we can control its mobility
and identify genes with expressions that are
modified by its insertion, leading to drug
resistance.
Selected Publications:
Garnett MJ, Edelman EJ, Heidorn
SJ, Greenman CD, Dastur A, Lau
KW, Greninger P, Thompson IR, Luo
X, Soares J, Liu Q, Iorio F, Milano
RJ, Bignell GR, Tam AT, Davies H,
Stevenson JA, Barthorpe S, Lutz SR,
McLaren-Douglas A, Mitropoulos
X, Mironenko T, Thi H, Richardson L,
Zhou W, Jewitt F, Zhang T, O’Brien
P, Price S, Hur W, Yang W, Deng X,
Butler A, Choi HG, Chang JW, Baselga
J, Stamenkovic I, Engelman JA,
Sharma SV, Saez-Rodriguez J, Gray
NS, Settleman J, Futreal PA, Haber
DA, Stratton MR, Ramaswamy S,
McDermott U, Benes CH. Systematic
identification of drug sensitivity
genomic markers in cancer cells.
Nature. 483(7391):507-5, 2012, Mar 28.
Singh A, Sweeney MF, Yu M, Burger
A, Greninger P, Benes C, Haber
D, Settleman J. TAK1 (MAP3K7)
inhibition promotes apoptosis in
KRAS-dependent colon cancers.
Cell. 148(4):639-50, 2012 Feb 17.
Benes CH, Poulogiannis G, Cantley
LC, Soltoff SP. The SRC-associated
protein CUB Domain-Containing
Protein-1 regulates adhesion and
motility. Oncogene. 2011 Jul 4.
Katayama R, Khan TM, Benes C,
Lifshits E, Ebi H, Rivera VM,
Shakespeare WC, Iafrate AJ,
Engelman JA, Shaw AT. Therapeutic
strategies to overcome crizotinib
resistance in non-small cell lung
cancers harboring the fusion
oncogene EML4-ALK. Proc Natl
Acad Sci U S A. 108(18):7535-40,
2011 May 3.
Yuan TL, Choi HS, Matsui A, Benes C,
Lifshits E, Luo J, Frangioni JV, Cantley
LC. Class 1A PI3K regulates vessel
integrity during development and tumorigenesis.
Proc Natl Acad Sci U S A.
105(28):9739-44, 2008 Jul 15.
Benes CH, Wu N, Elia AE, Dharia T,
Cantley LC, Soltoff SP. The C2 domain
of PKCdelta is a phosphotyrosine
binding domain. Cell. 121(2):271-80,
2005 Apr 22.
Principal Investigators
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