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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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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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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
“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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Citations
Cites
PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer
Hartkopf, A. D., Taran, F., Wallwiener, M., Walter, C. B., Krämer, B., Grischke, E., & Brucker, S. Y. (2016) · Breast Care · doi:10.1159/000453569 · Cited by 30,989
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)
Eisenhauer, E. A., Therasse, P., Bogaerts, J., Schwartz, L. H., Sargent, D., Ford, R., Dancey, J., Arbuck, S., Gwyther, S., Mooney, M., et al. (2009) · European Journal of Cancer · doi:10.1016/j.ejca.2008.10.026 · Cited by 29,534
The blockade of immune checkpoints in cancer immunotherapy
Pardoll, D. M. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3239 · Cited by 13,838
Nishimura, R., Osako, T., Nishiyama, Y., Tashima, R., Nakano, M., Fujisue, M., Toyozumi, Y., & Arima, N. (2013) · Oncology · doi:10.1159/000353099 · Cited by 13,239
Comprehensive molecular portraits of human breast tumours
The Cancer Genome Atlas Network (2012) · Nature · doi:10.1038/nature11412 · Cited by 12,129
Integrated genomic analyses of ovarian carcinoma
Perou, C. M. (2019) · Carolina Digital Repository (University of North Carolina at Chapel Hill) · doi:10.17615/hvp3-wg08 · Cited by 7,927
A Simple Practice Guide for Dose Conversion between Animals and Human
Nair, A., & Jacob, S. (2016) · Journal of Basic and Clinical Pharmacy · doi:10.4103/0976-0105.177703 · Cited by 6,174
Mutational landscape and significance across 12 major cancer types
Kandoth, C., McLellan, M. D., Vandin, F., Ye, K., Niu, B., Lu, C., Xie, M., Zhang, Q., McMichael, J. F., Wyczalkowski, M. A., et al. (2013) · Nature · doi:10.1038/nature12634 · Cited by 4,419
Zehir, A., Benayed, R., Shah, R. H., Syed, A., Middha, S., Kim, H. R., Srinivasan, P., Gao, J., Chakravarty, D., Devlin, S. M., et al. (2017) · Nature Medicine · doi:10.1038/nm.4333 · Cited by 3,380
Hingorani, S. R., Wang, L., Multani, A. S., Combs, C., Deramaudt, T. B., Hruban, R. H., Rustgi, A. K., Chang, S., & Tuveson, D. A. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.04.023 · Cited by 2,609
Cited by
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Items 301–319 of 319
Kim, J., & Kang, S. (2026) · Pharmaceutics · doi:10.3390/pharmaceutics18080934
“Because SHP2 functions as a critical mediator of RTK-driven RAS pathway reactivation, combined KRAS and SHP2 inhibition has demonstrated synergistic antitumor activity in preclinical PDAC models [49].”
Genetic and epigenetic modifiers of metastasis: Context matters
Welch, D. R., Swancutt, K. L., Walsh, R. M., & Fisette, G. (2026) · Quarterly Reviews of Biophysics · doi:10.1017/s0033583526100201
Li, Y., Xie, S., Sun, X., Wang, F., Guo, H., Chen, D., 党建华, Yang, X., Wang, Y., & Ma, X. (2026) · Frontiers in Oncology · doi:10.3389/fonc.2026.1927414
Shen, G., Wang, Y., Li, S., Liu, X., Luo, F., Dong, Q., Cui, L., & Lv, C. (2026) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2026.110435
Chen, Y.-L., Chen, W.-C., Yeh, T., Ho, H.-H., Chen, T.-C., & Wang, W. (2026) · Biomedical Journal · doi:10.1016/j.bj.2026.101036
Chatterjee, S., Arya, S., Sharma, N., Grover, M., Yadav, D., & Parveen, H. (2026) · Medical Oncology · doi:10.1007/s12032-026-03392-6
Ali, A. B., Gharbi, S., & Jebali, N. (2025) · Archive of International Journal of Cancer and Allied Science · doi:10.51847/r5z9g6bgrj
Alrawashdeh, A. Y., Chen, X., Hafner, P., Keller, S. J., Das, T., Jumaa, H., Avery, T. Y., Besson, S., Hempel, S., Mewes, S., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.05.23.727401
“…only substances targeting downstream effectors of KRAS, such as MEK1/2 or ERK1/2, had been available, but largely failed to demonstrate improved outcomes, often due to receptor tyrosine kinase (RTK)-dependent feedback-activation, resulting in reestablishment of downstream signaling 10,11 .”
Hamidi, A. A., Moaven, O., Mahmoudian, R. A., & Abbaszadegan, M. R. (2026) · Experimental Hematology and Oncology · doi:10.1186/s40164-026-00849-2
“…SOS1 inhibitors can reduce RTK-driven RAS reactivation and deepen pathway suppression, particularly with GDP-state inhibitors, but may affect immune and hematopoietic compartments and may be less effective in Q61-mutant tumors that are relatively independent of nucleotide exchange [94, 187, 188].”
InfluentialBindingDB Entry 50015652: Discovery of 6-[(3
BindingDB (2023) · UC San Diego · doi:10.7270/q2js9vc6
BindingDB (2024) · UC San Diego · doi:10.7270/q2ww7nvc
BindingDB Entry 50022804: Advances in SHP2 tunnel allosteric inhibitors and bifunctional molecules.
BindingDB (2026) · UC San Diego · doi:10.7270/q2v98dw4
BindingDB Entry 50016243: Strategies Targeting Protein Tyrosine Phosphatase SHP2 for Cancer Therapy.
BindingDB (2023) · UC San Diego · doi:10.7270/q2x92g9p
Uncovering KRAS -mutant allele-specific biology and vulnerabilities in non-small cell lung cancer
d’Arienzo, P. D., McDaid, W. J., Tinsley, K. L., Chen, T., Gasson, E. J., Lindsay, C. R., & Malliri, A. (2026) · Biochemical Journal · doi:10.1042/bcj20250138
“…et al. provided a mechanistic rationale for the difference in SHP2 inhibitor activity between KRAS mutants, showing that KRAS mutations with intact GTPase activity, such as KRAS G12C , were susceptible to SHP099, whereas those with abolished GTPase activity ( KRAS Q61R ) were resistant [115].”
Li, J., Zhang, N., Piao, M., Zhao, J., Wang, Y., Li, C., Li, S., Huang, Z., Li, Y., Xun, Z., et al. (2026) · Cancer and Metastasis Reviews · doi:10.1007/s10555-026-10392-5
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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