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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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BackgroundLi, Y., Yuan, Y., Zhang, F., Guo, A., Cao, F., Song, M., Fu, Y., Xu, X., Shen, H., Zheng, S., et al. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.739501 · Cited by 17
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BackgroundResultInfluentialAP1/Fra1 confers resistance to MAPK cascade inhibition in pancreatic cancer
Schneeweis, C., Diersch, S., Hassan, Z., Krauß, L., Schneider, C., Lucarelli, D., Falcomatà, C., Steiger, K., Öllinger, R., Krämer, O. H., et al. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04638-y · Cited by 19
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“Inactivation of SHP2 and MEK inhibitor treatment resulted in a more sustained inhibition of the pathway, reducing resistance to inhibition of MEK (Fedele et al., 2018).”
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“SHP2 phosphatase has been an attractive antitumor target, mainly because of its key role as a signal transduction node downstream of multiple RTKs and, subsequently, as a positive regulator of RAS and MAPK signaling [153–155].”
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Rational combination of SHP2 and mTOR inhibition for the treatment of hepatocellular carcinoma
Mulero‐Sánchez, A., Ramirez, C. F. A., du Chatinier, A., Wang, H., Koomen, S. J. I., Song, J., de Groot, M. H. P., Lieftink, C., Bosma, A. R., Burylo, A. M., et al. (2023) · Molecular Oncology · doi:10.1002/1878-0261.13377 · Cited by 14
Miao, Y., Bai, Y., Miao, J., Murray, A. A., Lin, J., Dong, J., Qu, Z., Zhang, R., Nguyen, Q. D., Wang, S., et al. (2024) · Journal of Clinical Investigation · doi:10.1172/jci177142 · Cited by 17
“Moreover, some SHP2-AIs also display unexpected activity against the so-called RAS bypass cancers, which harbor RAS or RAF mutations known to be independent of upstream signaling from SHP2 (23, 26, 27, 33, 38).”
InfluentialKang, D., Wang, Y., Lin, Y., Ma, W. W., Morgensztern, D., Leventakos, K., Bi, C., Ding, Y., Xiong, J., Yan, M., et al. (2025) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-24-3691 · Cited by 17
Lu, J. G., Hu, M., Zhao, Y., Chu, T., Zhang, W., Zhou, Y., Cai, X., Wu, J., Hu, L., Shi, C., et al. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02382-w · Cited by 14
“17,18,21,22,46 49 In our study, treatment with the MEK inhibitor trametinib plus the RTK inhibitor anlotinib markedly decreased the tumor burden of targeted lesions in a phase I cohort of 33 advanced NSCLC patients harboring various non-G12C KRAS mutations.”
Godfrey, L., Förster, J., Liffers, S., Schröder, C., Köster, J., Henschel, L., Ludwig, K. U., Laehnemann, D., Trajkovic‐Arsic, M., Behrens, D., et al. (2024) · Clinical Epigenetics · doi:10.1186/s13148-024-01623-z · Cited by 15
“Several cellular processes including mitochondrial function, nucleotide synthesis, protective autophagy or the deregulation of YAP, SHP or ERBB have been reported to be involved in MEK i resistance [12–19].”
BackgroundToledo, B., Deiana, C., Scianò, F., Brandi, G., Marchal, J. A., Perán, M., & Giovannetti, E. (2024) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2024.2319340 · Cited by 15
“…the use of SHP2 inhibitors (SHP099), MEK inhibitors (cobimetinib), and KRAS-G12C inhibitors (sotorasib), can enhance the efficacy of chemotherapeutic agents in PC cells carrying KRAS mutations, as well as an acceptable safety profile in pretreated patients with KRAS-mutated advanced PC [59–61].”
BackgroundSun, R., Tu, X., Chan, S., Wang, X., Ji, Y., Wang, Z., Yu, Z., Zuo, X., Zhang, Q. H., Chen, J., et al. (2024) · Journal of Cancer · doi:10.7150/jca.92633 · Cited by 14
“[ 11,12] It consists of three classical branches: ERK, JNK, and p38 MAPK.”
BackgroundZhu, C., Zhao, H., Yang, W., Chen, K., Liu, X., Yu, Y., Li, R., Tan, R., & Yu, Z. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c01217 · Cited by 14
Bontoux, C., Hofman, V., Brest, P., Ilié, M., Mograbi, B., & Hofman, P. M. (2022) · Cancers · doi:10.3390/cancers14071628 · Cited by 17
KRASG12C inhibitor: combing for combination
Chakraborty, A. (2020) · Biochemical Society Transactions · doi:10.1042/bst20200473 · Cited by 15
Gu, Y., Wei, C., Chung, M., Li, H., Guo, Z., Long, M., Li, Y., Wang, W., Aimaier, R., Li, Q., et al. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.910505 · Cited by 13
“Frontiers in Oncology 10 Targeting the key pathways of drug resistance is an effective way to improve the sensitivity of cancers, which is of great significance for improving the survival rate of patients with advanced tumors (18, 59).”
BackgroundSynergistic anticancer effect by targeting CDK2 and EGFR–ERK signaling
Wu, J., Chen, Y., Li, R., Guan, Y., Chen, M. H., Yin, H., Yang, X., Jin, M., Huang, B., Ding, X., et al. (2023) · The Journal of Cell Biology · doi:10.1083/jcb.202203005 · Cited by 14
“In addition, reactivation of ERK1/2 is a primary reason for chemoresistance after treatment with EGFR, KRAS, BRAF, and MEK inhibitors (Fedele et al., 2018; Morris et al., 2013; Sanchez et al., 2019; Tadesse et al., 2020; Yu et al., 2015; Zhang et al., 2021a), suggesting that targeting ERK1/2…”
Popescu, B. O., Stahlhut, C. E., Tarver, T. C., Wishner, S., Lee, B. J., Peretz, C. A. C., Luck, C., Phojanakong, P. J., Cámara, J. A., Hongo, H., et al. (2023) · Cell Reports Medicine · doi:10.1016/j.xcrm.2023.101290 · Cited by 12
“33 Giventhepivotal role of SHP2 in RTK signaling, we hypothesize that SHP2 inhibition has activity in multiple subtypes of RTK-driven AML and suppresses key mechanisms of tyrosine kinase inhibitor(TKI)resistancedependentonactivatedMAPKsignaling,…”
BackgroundLu, X., Yu, R., Li, Z., Yang, M., Dai, J., & Liu, M. (2023) · Cancer Letters · doi:10.1016/j.canlet.2023.216517 · Cited by 13
Gupta, K., Jones, J. C., Farias, V., Mackeyev, Y., Singh, P. K., Quiñones‐Hinojosa, A., & Krishnan, S. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.840241 · Cited by 12
Kim, B., Jo, S., Park, S. B., Chae, C. H., Lee, K., Koh, B., & Shin, I. (2019) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2019.126756 · Cited by 13
The Discovery of Cryptic Pockets Increases the Druggability of “Undruggable” Proteins
Mou, M., Yang, W., Huang, G., Yang, X., Zhang, X. L., Kandegama, W., Ashby, C. R., Hao, G., & Gao, Y. (2025) · Medicinal Research Reviews · doi:10.1002/med.70001 · Cited by 14
Li, Z., Wang, S., Han, J., Shi, C., Yang, G., Cui, Y., Xi, L., Yin, S., & Zhang, H. (2023) · Journal of Proteomics · doi:10.1016/j.jprot.2023.104938 · Cited by 12
Liu, P., Li, Y., Li, M., Zhou, H., Zhang, H., Zhang, Y., Xu, J., Xu, Y. L., Zhang, J., Xia, B., et al. (2022) · iScience · doi:10.1016/j.isci.2022.103867 · Cited by 12
PTPRS drives adaptive resistance to MEK/ERK inhibitors through SRC
Davis, T. B., Yang, M., Wang, H., Lee, C., Yeatman, T. J., & Pledger, W. J. (2019) · Oncotarget · doi:10.18632/oncotarget.27335 · Cited by 11
Complex Roles of PTPN11/SHP2 in Carcinogenesis and Prospect of Targeting SHP2 in Cancer Therapy
Scheiter, A., Lu, L., Gao, L. H., & Feng, G. (2023) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-062722-013740 · Cited by 13
Chen, J., Dai, J., Kang, Z., Yang, T., Zhao, Q., Zheng, J., Zhang, X., Zhang, J., Xu, J., Sun, G., et al. (2020) · Experimental Cell Research · doi:10.1016/j.yexcr.2020.112060 · Cited by 11
Antigen Peptide Transporter 1 (TAP1) Promotes Resistance to MEK Inhibitors in Pancreatic Cancers
Li, X., Feng, Y. C., Hou, Q., Fu, Y., & Luo, Y. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23137168 · Cited by 11
“Our previous data showed that TAP1 suppression decreased the reactivation of ERK phosphorylation, which was consistent with SHP2 inhibitors which blocked the adaptive increase in ERK phosphorylation [37].”
ResultSütcüoğlu, O., Yıldırım, H. Ç., Almuradova, E., Günenç, D., & Yalçın, Ş. (2025) · Medicina · doi:10.3390/medicina61071202 · Cited by 10
“In addition, it has been shown that SHP2 inhibitors effectively overcome adaptive resistance to MEK inhibitors in KRAS mutant cancers [70,71].”
Sait, S. F., Tang, K. H., Angus, S. P., Brown, R. M., Sun, D., Xie, X., Iltis, C., Lien, M. C., Socci, N. D., Bale, T., et al. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2407745121 · Cited by 10
Self-citationDay, E. K., Zhong, Q., Purow, B. W., & Lazzara, M. J. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-1756 · Cited by 10
“Allosteric SHP2 inhibitors such as SHP099 and TNO155 are now available and may help overcome adaptive resistance such as ERK reactivation after MEK inhibition in carcinomas (6).”
BackgroundOvercoming MET-mediated resistance in oncogene-driven NSCLC
Reischmann, N., Schmelas, C., Molina‐Vila, M. Á., Jordana‐Ariza, N., Kuntze, D., García-Román, S., Simard, M. A., Musch, D., Esdar, C., Albers, J., et al. (2023) · iScience · doi:10.1016/j.isci.2023.107006 · Cited by 10
Pan, R., Dai, J., Liang, W., Wang, H., Ye, L., Ye, S., Lin, Z., Huang, S., Xiong, Y., Zhang, L., et al. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-05885-y · Cited by 9
Élez, E., Cubillo, A., Alfonso, P., Middleton, M. R., Chau, I., Alkuzweny, B., Alcasid, A., Zhang, X., & Cutsem, E. V. (2024) · BMC Cancer · doi:10.1186/s12885-024-12153-5 · Cited by 12
“Despite the lack of efficacy results in this study, MEK inhibitors still have promise in MSS mCRC and are currently being tested with broader inhibitors upstream of MEK1/2 in the RAS-regulated RAF–MEK1/2–ERK pathway, including drugs targeting SHP2 and SOS [35, 36].”
BackgroundDichotomous role of Shp2 for naïve and primed pluripotency maintenance in embryonic stem cells
Kim, S.-M., Kwon, E., Kim, Y.-J., Go, Y.-H., Oh, J., Park, S., Tae, J., Kim, K.-T., & Cha, H. (2022) · Stem Cell Research & Therapy · doi:10.1186/s13287-022-02976-z · Cited by 9
“Considering the positive role of Shp2 in Ras-dependent Erk activation (Ras-to-Erk), as well as in oncogenic Ras-to-Erk [21, 22] and target therapy resistance [23], small molecules to inhibit the bivalent roles of Shp2 have been developed as novel anti-cancer therapeutic agents [24].”
BackgroundProtein tyrosine phosphatases: emerging role in cancer therapy resistance
Zhao, M., Shuai, W., Su, Z., Xu, P., Wang, A., Sun, Q., & Wang, G. (2024) · 癌症：英文版 · doi:10.1002/cac2.12548 · Cited by 9
“Scientists also claimed that combination therapy of trametinib and SHP-099 (SHP2 inhibitor) benefited to impeding ERK reactivation in response to MEK inhibition, resulting in sustained growth inhibition in KRAS-mutated PDAC [18].”
BackgroundExploring the Clinical Impact of Predictive Biomarkers in Serous Ovarian Carcinomas
Page, C. L., Chung, J. W., Rahimi, K., Köbel, M., Provencher, D. M., & Mes‐Masson, A. (2019) · Current Drug Targets · doi:10.2174/1389450120666191016143836 · Cited by 9
KRAS G12C inhibition and innate immune targeting
Tani, T., Kitajima, S., Conway, E. B., Knelson, E. H., & Barbie, D. A. (2021) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2021.1902991 · Cited by 9
“SHP2 inhibitors are also being tested in combination with MEK inhibitors to prevent acquired resistance [27].”
BackgroundTargeting PDGFRA-SHP2 signaling enhances radiotherapy in IDH1-mutant glioma
Yu, X., Song, X., Tiek, D. M., Wu, R., Walker, M. N., Horbinski, C., Hu, B., & Cheng, S. (2025) · Neuro-Oncology · doi:10.1093/neuonc/noaf086 · Cited by 8
Setting sail: Maneuvering SHP2 activity and its effects in cancer
Welsh, C. L., Allen, S., & Madan, L. K. (2023) · Advances in cancer research · doi:10.1016/bs.acr.2023.03.003 · Cited by 9
WWP1 inhibition increases SHP2 inhibitor efficacy in colorectal cancer
Fan, H., Hu, X., Cao, F., Zhou, L., Wen, R., Shen, H., Fu, Y., Zhu, X., Jia, H., Liu, Z., et al. (2024) · npj Precision Oncology · doi:10.1038/s41698-024-00650-6 · Cited by 9
Yi, J., Tian, M., Hu, L., Kang, N., Ma, W., Zhi, J., Zheng, X., Ruan, X., & Gao, M. (2021) · Annals of Translational Medicine · doi:10.21037/atm-21-1854 · Cited by 8
Combined Omipalisib and MAPK Inhibition Suppress PDAC Growth
Bye, B. A., Jack, J. L., Pierce, A., Walsh, R. M., Eades, A. E., Chalise, P., Olou, A. A., & VanSaun, M. N. (2025) · Cancers · doi:10.3390/cancers17071152 · Cited by 15
“As part of a combination therapeutic strategy, targeting SHP2 via a selective inhibitor such as SHP099 [43] effectively inhibited the MAPK pathway and counteracted therapeutic resistance when combined with a MEK inhibitor in mutant KRAS-driven cancers [44–47].”
Therapeutic potential of targeting protein tyrosine phosphatases in liver diseases
Wang, A., Zhang, Y., Lv, X., & Liang, G. (2024) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2024.05.006 · Cited by 7
“For example, combining SHP2 inhibitors with MEK inhibitors might benefit patients with KRAS-mutant pancreatic cancer 75 , non-small cell lung cancer (NSCLC) 76 , and triple-negative breast cancer 77 .”
BackgroundLiu, Y., Wu, L., Lü, H., Wu, E., Ni, J., & Zhou, X. (2021) · Journal of Oncology · doi:10.1155/2021/2721466 · Cited by 7
“SHP2 is an adaptor required for the signal transduction of multiple RTKs (Figure 3(d)) [26]; however, cotreatment with ARS-1620 and SHP-099 did not reduce the viability of H358_R cells (Figure 3(e)).”
BackgroundThe insulin receptor endocytosis
Wu, J., Park, S. H., & Choi, E. (2022) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2022.06.020 · Cited by 7
TargetingKRAS G12Cmutations in colorectal cancer
Zhao, M., & Wu, A. (2022) · Gastroenterology report · doi:10.1093/gastro/goac083 · Cited by 9
Chen, L., Zhao, W., Li, M., Yang, Y., Tian, C., Zhang, D., Chang, Z., Zhang, Y., Zhao, Z. J., Chen, Y., et al. (2023) · Reproduction · doi:10.1530/rep-22-0367 · Cited by 7
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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