Synthetic Lethal Interaction of SHOC2 Depletion with MEK Inhibition in RAS-Driven Cancers
Rita Sulahian,
Jason J. Kwon,
Katherine H. Walsh,
Emma Pailler,
Timothy L. Bosse,
Maneesha Thaker,
Diego Almanza,
Joshua M. Dempster,
Joshua Pan,
Federica Piccioni,
Nancy Dumont,
Alfredo Gonzalez,
Jonathan Rennhack,
Behnam Nabet,
John A. Bachman,
Amy Goodale,
Yenarae Lee,
Mukta Bagul,
Rosy Liao,
Adrija Navarro,
Tina L. Yuan,
Raymond W.S. Ng,
Srivatsan Raghavan,
Nathanael S. Gray,
Aviad Tsherniak,
Francisca Vazquez,
David E. Root,
Ari J. Firestone,
Jeff Settleman,
William C. Hahn,
Andrew J. Aguirre
Affiliations
Rita Sulahian
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Jason J. Kwon
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Katherine H. Walsh
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Emma Pailler
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Timothy L. Bosse
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Maneesha Thaker
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Diego Almanza
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Joshua M. Dempster
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Joshua Pan
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Federica Piccioni
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Nancy Dumont
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Alfredo Gonzalez
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Jonathan Rennhack
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Behnam Nabet
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA
John A. Bachman
Laboratory of Systems Pharmacology, Harvard Medical School, 200 Longwood Ave., Boston, MA 02115, USA
Amy Goodale
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Yenarae Lee
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Mukta Bagul
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Rosy Liao
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Adrija Navarro
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Tina L. Yuan
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Raymond W.S. Ng
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Srivatsan Raghavan
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
Nathanael S. Gray
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA
Aviad Tsherniak
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Francisca Vazquez
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
David E. Root
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Ari J. Firestone
Calico Life Sciences, South San Francisco, CA 94080, USA
Jeff Settleman
Calico Life Sciences, South San Francisco, CA 94080, USA
William C. Hahn
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; Corresponding author
Andrew J. Aguirre
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; Corresponding author
Summary: 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. : Sulahian, Kwon, and Walsh et al. performed several loss-of-function CRISPR-Cas9 screens in KRAS-mutant cancer cells treated with a MEK inhibitor and define the landscape of modifiers of MEK inhibitor sensitivity while highlighting that SHOC2 is a potent synthetic lethal target that serves as a critical signaling node to mediate MAP kinase pathway reactivation upon MEK inhibition. Keywords: Ras, KRAS, MEK inhibitor, synthetic lethal, SHOC2, CRISPR-Cas9 screen
