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SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models
Open accessPublished version of a preprint
Abstract
Adaptive resistance to MEK inhibitors (MEKi) typically occurs via induction of genes for different receptor tyrosine kinases (RTK) and/or their ligands, even in tumors of the same histotype, making combination strategies challenging. SHP2 (PTPN11) is required for RAS/ERK pathway activation by most RTKs and might provide a common resistance node. We found that combining the SHP2 inhibitor SHP099 with a MEKi inhibited the proliferation of multiple cancer cell lines in vitro. PTPN11 knockdown/MEKi treatment had similar effects, whereas expressing SHP099 binding–defective PTPN11 mutants conferred resistance, demonstrating that SHP099 is on-target. SHP099/trametinib was highly efficacious in xenograft and/or genetically engineered models of KRAS-mutant pancreas, lung, and ovarian cancers and in wild-type RAS-expressing triple-negative breast cancer. SHP099 inhibited activation of KRAS mutants with residual GTPase activity, impeded SOS/RAS/MEK/ERK1/2 reactivation in response to MEKi, and blocked ERK1/2-dependent transcriptional programs. We conclude that SHP099/MEKi combinations could have therapeutic utility in multiple malignancies. Significance: MEK inhibitors show limited efficacy as single agents, in part because of the rapid development of adaptive resistance. We find that SHP2/MEK inhibitor combinations prevent adaptive resistance in multiple cancer models expressing mutant and wild-type KRAS. Cancer Discov; 8(10); 1237–49. ©2018 AACR. See related commentary by Torres-Ayuso and Brognard, p. 1210. This article is highlighted in the In This Issue feature, p. 1195
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“Indeed, inhibition of SHP2 was recently shown to overcome RTK-driven adaptive feedback mechanisms to MEK inhibition, and enhance the efficacy of MEK inhibitor induced growth suppression in vitro and in vivo in RAS-driven cancers (27,41–44).”
From Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition (2020) · cites this paper as [41]
In the citing paper
“the heterogeneity of RTK/RTK ligand activation renders combination therapies with MAPKi and RTKi unfeasible [33]”
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 [33]
In the citing paper
“several studies have shown that similar pathway reactivation occurs upon KRASG12C-inhibitor treatment50,110–113.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [111]
In the citing paper
“In addition, it has been shown that SHP2 inhibitors effectively overcome adaptive resistance to MEK inhibitors in KRAS mutant cancers [70,71].”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [70]
In the citing paper
“Recently, several groups, including ours, provided strong evidence that SHP2 acts upstream of SOS1/SOS2 to regulate exchange; consequently, SHP2-Is abrogate adaptive resistance to BRAF or MEK inhibitors (Ahmed et al., 2019; Fedele et al., 2018; Hao et al., 2019; Mainardi et al., 2018; Nichols et al., 2018).”
From SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling (2021) · cites this paper as Fedele et al., 2018
In the citing paper
“Recently, several groups, including ours, provided strong evidence that SHP2 acts upstream of SOS1/SOS2 to regulate exchange; consequently, SHP2-Is abrogate adaptive resistance to BRAF or MEK inhibitors (Ahmed et al., 2019; Fedele et al., 2018; Hao et al., 2019; Mainardi et al., 2018; Nichols et al., 2018).”
From SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling (2021) · cites this paper as Fedele et al., 2018
In the citing paper
“Allosteric SHP2-Is (e.g., SHP099) reduce the activation of KRAS mutants with residual GTPase activity (“cycling mutants”), most notably KRASG12C and, to a lesser extent, KRASG12D and KRASG12V (hereafter G12C, G12D, and G12V) in cancer cell lines and reconstituted “RAS-less” MEFs (Ahmed et al., 2019; Fedele et al., 2018; Hao et al., 2019; Mainardi et al., 2018; Nichols et al., 2018).”
From SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling (2021) · cites this paper as Fedele et al., 2018
In the citing paper
“As we reported previously (Fedele et al., 2018), SHP099 decreased KCP tumor vascularity, as shown by CD31 immunostaining.”
From SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling (2021) · cites this paper as Fedele et al., 2018
In the citing paper
“SHP099-resistant KCP pancreas tumors showed marked decreases in tumor vasculature in response to SHP099, similar to parental (Fedele et al., 2018) and WT-PTPN11–reconstituted (Fig. 7 D) cells.”
From SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling (2021) · cites this paper as Fedele et al., 2018
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Metadata
- Authors
- Fedele, C., Ran, H., Diskin, B., Wei, W., Jen, J., Geer, M. J., Araki, K., Ozerdem, U., Simeone, D. M., Miller, G., Neel, B. G., & Tang, K. H.
- Affiliations
- NYU Langone Health (US)
- 3Department of Pathology, New York University School of Medicine, NYU Langone Health, New York, New York.
- Corresponding author
- Fedele, Carmine
- Neel, Benjamin G.
- Tang, Kwan Ho
- ORCID
- Venue
- Cancer Discovery
- Published
- 2018-10-01
- Volume
- 8
- Issue
- 10
- Pages
- 1237-1249
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC6170706
- OpenAlex
- W2883433181
- Semantic Scholar
- 3bca0817b635832625416941ad870fcfe16a4a69
- Cited by
- 315
- References
- 53
- Citations by year
- 2026: 26 · 2025: 32 · 2024: 39 · 2023: 45 · 2022: 51 · 2021: 54 · 2020: 38 · 2019: 27 · 2018: 3
- FWCI
- 10.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- HHS | National Institutes of Health (NIH) (R01CA049152, R01CA131045)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- 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
- Keywords
- SHP2, PTPN11, MEK inhibitors, adaptive drug resistance, SHP099, trametinib, KRAS mutation, Ras/ERK pathway, receptor tyrosine kinase, triple-negative breast cancer, pancreatic cancer, lung cancer, ovarian cancer, combination therapy, SOS1
- MeSH terms
- Animals, Humans, Mitogen-Activated Protein Kinase Kinases, Xenograft Model Antitumor Assays, Protein Kinase Inhibitors, Mice, Protein Tyrosine Phosphatase, Non-Receptor Type 11
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