Marked synergy by vertical inhibition of EGFR signaling in NSCLC spheroids shows SOS1 is a therapeutic target in EGFR-mutated cancer
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Abstract
Drug treatment of 3D cancer spheroids more accurately reflects in vivo therapeutic responses compared to adherent culture studies. In EGFR-mutated lung adenocarcinoma, EGFR-TKIs show enhanced efficacy in spheroid cultures. Simultaneous inhibition of multiple parallel RTKs further enhances EGFR-TKI effectiveness. We show that the common RTK signaling intermediate SOS1 was required for 3D spheroid growth of EGFR-mutated NSCLC cells. Using two distinct measures of pharmacologic synergy, we demonstrated that SOS1 inhibition strongly synergized with EGFR-TKI treatment only in 3D spheroid cultures. Combined EGFR- and SOS1-inhibition markedly inhibited Raf/MEK/ERK and PI3K/AKT signaling. Finally, broad assessment of the pharmacologic landscape of drug-drug interactions downstream of mutated EGFR revealed synergy when combining an EGFR-TKI with inhibitors of proximal signaling intermediates SOS1 and SHP2, but not inhibitors of downstream RAS effector pathways. These data indicate that vertical inhibition of proximal EGFR signaling should be pursued as a potential therapy to treat EGFR-mutated tumors.
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Preclinical data show synergistic antiproliferative effects and enhanced antitumor efficacy for SHP2 inhibitor/KRASG12C inhibitor and SOS1 inhibitor/KRASG12C inhibitor combinations.
“Preclinical data has demonstrated synergistic antiproliferative effects and enhanced antitumor efficacy for both the SHP2 inhibitor/KRASG12C inhibitor combination (43) and the SOS1 inhibitor/KRASG12C inhibitor combination (44, 45).”
From Expanding the Reach of Precision Oncology by Drugging All <i>KRAS</i> Mutants (2022) · cites this paper as [44]
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Targeting KRAS in Pancreatic Cancer
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Breaking Oncogene Addiction: Getting RTK/RAS-Mutated Cancers off the SOS
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The Next Generation of KRAS Targeting: Reasons for Excitement and Concern
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In situ modeling of acquired resistance to RTK/RAS-pathway-targeted therapies
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Cytotoxic activity of KRAS inhibitors in combination with chemotherapeutics
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Self-citationWild-type RAS signaling is an essential therapeutic target in RAS -mutated cancers
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HRAS promotes mutant NRAS–driven transformation with codon and allele specificity
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- Authors
- Theard, P. L., Sheffels, E., Sealover, N. E., Linke, A. J., Pratico, D. J., & Kortum, R. L.
- Affiliations
- Uniformed Services University of the Health Sciences (US)
- Corresponding author
- Kortum, Robert L
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2020-09-08
- Volume
- 9
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC7478890
- OpenAlex
- W3084211591
- Cited by
- 69
- References
- 67
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 13 · 2023: 11 · 2022: 14 · 2021: 15 · 2020: 2
- FWCI
- 6.06
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Congressionally Directed Medical Research Programs (LC160222, LC180213)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Keywords
- EGFR mutation, non-small cell lung cancer, SOS1, SHP2, EGFR tyrosine kinase inhibitors, drug synergy, MAPK/ERK pathway, PI3K/Akt signaling, Ras effector pathways, lung adenocarcinoma
- MeSH terms
- Acrylamides, Aniline Compounds, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Drug Synergism, Humans, Indoles, Lung Neoplasms, Mutation, Pyrimidines, Signal Transduction, Apoptosis, Spheroids, Cellular, SOS1 Protein, Cell Line, Tumor, Cell Proliferation, HEK293 Cells, ErbB Receptors
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