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

doi:10.1016/j.celrep.2019.08.090

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

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

Authors

Rita Sulahian¹, Jason J Kwon², Katherine H Walsh¹, Emma Pailler², Timothy L Bosse¹, Maneesha Thaker¹, Diego Almanza¹, Joshua M Dempster¹, Joshua Pan², Federica Piccioni¹, Nancy Dumont¹, Alfredo Gonzalez¹, Jonathan Rennhack², Behnam Nabet³, John A Bachman⁴, Amy Goodale¹, Yenarae Lee¹, Mukta Bagul¹, Rosy Liao¹, Adrija Navarro¹, Tina L Yuan¹, Raymond W S Ng¹, Srivatsan Raghavan⁵, Nathanael S Gray³, Aviad Tsherniak¹, Francisca Vazquez¹, David E Root¹, Ari J Firestone⁶, Jeff Settleman⁶, William C Hahn⁷, Andrew J Aguirre⁸

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

A549 Cells
Animals
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Proliferation / physiology
HCT116 Cells
Humans
Intracellular Signaling Peptides and Proteins / metabolism*
MAP Kinase Signaling System / drug effects
MAP Kinase Signaling System / physiology*
Mice
Mice, Hairless
Mice, SCID
Mitogen-Activated Protein Kinases / metabolism*
Neoplasms / drug therapy
Neoplasms / metabolism*
Protein Kinase Inhibitors / pharmacology
Signal Transduction / drug effects
Signal Transduction / physiology
ras Proteins / metabolism*

Substances

Intracellular Signaling Peptides and Proteins
Protein Kinase Inhibitors
SHOC2 protein, human
Mitogen-Activated Protein Kinases
ras Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding