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Cell Rep. 2019 Oct 1;29(1):118-134.e8. doi: 10.1016/j.celrep.2019.08.090.

Synthetic Lethal Interaction of SHOC2 Depletion with MEK Inhibition in RAS-Driven Cancers.

Author information

1
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
2
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
3
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA.
4
Laboratory of Systems Pharmacology, Harvard Medical School, 200 Longwood Ave., Boston, MA 02115, USA.
5
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA.
6
Calico Life Sciences, South San Francisco, CA 94080, USA.
7
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, MA. Electronic address: william_hahn@dfci.harvard.edu.
8
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, MA. Electronic address: andrew_aguirre@dfci.harvard.edu.

Abstract

The mitogen-activated protein kinase (MAPK) pathway is a critical effector of oncogenic RAS signaling, and MAPK pathway inhibition may be an effective combination treatment strategy. We performed genome-scale loss-of-function CRISPR-Cas9 screens in the presence of a MEK1/2 inhibitor (MEKi) in KRAS-mutant pancreatic and lung cancer cell lines and identified genes that cooperate with MEK inhibition. While we observed heterogeneity in genetic modifiers of MEKi sensitivity across cell lines, several recurrent classes of synthetic lethal vulnerabilities emerged at the pathway level. Multiple members of receptor tyrosine kinase (RTK)-RAS-MAPK pathways scored as sensitizers to MEKi. In particular, we demonstrate that knockout, suppression, or degradation of SHOC2, a positive regulator of MAPK signaling, specifically cooperated with MEK inhibition to impair proliferation in RAS-driven cancer cells. The depletion of SHOC2 disrupted survival pathways triggered by feedback RTK signaling in response to MEK inhibition. Thus, these findings nominate SHOC2 as a potential target for combination therapy.

KEYWORDS:

CRISPR-Cas9 screen; KRAS; MEK inhibitor; Ras; SHOC2; synthetic lethal

PMID:
31577942
DOI:
10.1016/j.celrep.2019.08.090
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