Synthetic Lethal Interaction of SHOC2 Depletion with MEK Inhibition in RAS-Driven Cancers
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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.
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The feedback activations of redundant signaling mediated by RTKs confer MEKi resistance.
“The feedback activations of redundant signaling mediated by RTKs were considered to confer MEKi resistance in previous studies [17, 28, 31, 32].”
From Genome-wide CRISPR-cas9 knockout screening identifies GRB7 as a driver for MEK inhibitor resistance in KRAS mutant colon cancer (2022) · cites this paper as [28]
The mechanism of primary resistance in A549 and CFPAC-1 cells was reported to be activation of the RTK-mTOR signaling pathway.
“The mechanism of primary resistance in these cells was reported to be activation of the RTK-mTOR signaling pathway [28].”
From Genome-wide CRISPR-cas9 knockout screening identifies GRB7 as a driver for MEK inhibitor resistance in KRAS mutant colon cancer (2022) · cites this paper as [28]
SHOC2 was depleted in three of four cell lines.
“SHOC2, a known SL gene in MEK-inhibitor treated cells (32), was depleted in 3/4 lines”
From Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy (2023) · cites this paper as [32]
Genetic and pharmacological screens identified RTK signaling to PI3K and mTOR, and autophagy, as collateral dependencies with KRAS and MAPK pathway inhibitors.
“These experiments have identified receptor tyrosine kinase (RTK) signaling to PI3K and mTOR (23, 37–40), as well as the autophagy pathway (30) as collateral dependencies with KRAS and MAPK pathway inhibitors.”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [37]
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- Authors
- Sulahian, R., Kwon, J. J., Walsh, K. H., Pailler, E., Bosse, T. L., Thaker, M., Almanza, D., Dempster, J. M., Pan, J., Piccioni, F., Dumont, N., Gonzalez, A., Rennhack, J., Nabet, B., Bachman, J. A., Goodale, A., Lee, Y., Bagul, M., Liao, R., Navarro, A., Yuan, T. L., Ng, R. W. S., Raghavan, S., Gray, N. S., Tsherniak, A., Vazquez, F., Root, D. E., Firestone, A. J., Settleman, J., Hahn, W. C., & Aguirre, A. J.
- Affiliations
- Broad Institute (US)
- Harvard University (US)
- Calico Life Sciences (US)
- Corresponding author
- Hahn, William C.
- Aguirre, Andrew J.
- ORCID
- Kwon, Jason J.
- Pailler, Emma
- Bosse, Timothy L.
- Thaker, Maneesha
- Almanza, Diego
- Dempster, Joshua M.
- Pan, Joshua
- Piccioni, Federica
- Dumont, Nancy
- Gonzalez, Alfredo
- Rennhack, Jonathan
- Nabet, Behnam
- Bachman, John A.
- Goodale, Amy
- Lee, Yenarae
- Liao, Rosy
- Navarro, Adrija
- Yuan, Tina L.
- Ng, Raymond W.S.
- Raghavan, Srivatsan
- Gray, Nathanael S.
- Tsherniak, Aviad
- Root, David E.
- Firestone, Ari J.
- Hahn, William C.
- Aguirre, Andrew J.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2019-10
- Volume
- 29
- Issue
- 1
- Pages
- 118-134.e8
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC6918830
- OpenAlex
- W2979273775
- Cited by
- 90
- References
- 68
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 15 · 2023: 13 · 2022: 18 · 2021: 16 · 2020: 9
- FWCI
- 3.56
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Sanofi
- Doris Duke Charitable Foundation
- Pancreatic Cancer Action Network
- Harvard Catalyst (UL1 TR001102)
- Conquer Cancer Foundation (U01 CA199253, U01 CA224146, K08 CA218420-02, NIH-NCI K08 CA218420-02)
- American Cancer Society (PF-17-010-01-CDD)
- Astellas Pharma US
- Foghorn Therapeutics
- National Institutes of Health
- Hope Funds for Cancer Research
- Mirati Therapeutics
- Merck
- Takeda Pharmaceuticals U.S.A.
- National Cancer Institute (F32CA243290)
- Fondation pour la Recherche Médicale (SPE2018035027)
- Novartis
- Lustgarten Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- SHOC2, MEK inhibition, synthetic lethality, RAS-driven cancers, KRAS mutation, MAPK signaling, pancreatic cancer, lung cancer, receptor tyrosine kinase signaling, feedback signaling, combination therapy, CRISPR-Cas9 screen, cell proliferation
- MeSH terms
- A549 Cells, Animals, Humans, Mice, Hairless, Neoplasms, Signal Transduction, Mice, SCID, ras Proteins, Mitogen-Activated Protein Kinases, MAP Kinase Signaling System, HCT116 Cells, Cell Line, Tumor, Protein Kinase Inhibitors, Intracellular Signaling Peptides and Proteins, Cell Proliferation, Mice
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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