SHP2 inhibition prevents adaptive resistance to MEK inhibitors in multiple cancer models
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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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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.
“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]
The heterogeneity of RTK/RTK ligand activation renders combination therapies with MAPKi and RTKi unfeasible.
“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]
Several studies have shown that RAS-MAPK pathway reactivation occurs upon KRASG12C-inhibitor treatment.
“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]
SHP2 inhibitors effectively overcome adaptive resistance to MEK inhibitors in KRAS mutant cancers.
“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]
SHP2 acts upstream of SOS1/SOS2 to regulate RAS exchange.
“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
SHP2 inhibitors abrogate adaptive resistance to BRAF or MEK inhibitors.
“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
Allosteric SHP2-Is (e.g., SHP099) reduce activation of KRAS mutants with residual GTPase activity ('cycling mutants'), most notably KRASG12C and to a lesser extent KRASG12D and KRASG12V, in cancer cell lines and reconstituted RAS-less MEFs.
“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
SHP099 decreased KCP tumor vascularity.
“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
SHP099-resistant KCP pancreas tumors showed marked decreases in tumor vasculature in response to SHP099, similar to parental and WT-PTPN11-reconstituted cells.
“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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Duan, X.-P., Qin, B., Jiao, X., Liu, K., Wang, Z., & Zang, Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01760-0 · Cited by 217 · see citing works
Prebiotic-Induced Anti-tumor Immunity Attenuates Tumor Growth
Li, Y., Elmén, L., Segota, I., Xian, Y., Tinoco, R., Feng, Y., Fujita, Y., Segura Muñoz, R. R., Schmaltz, R., Bradley, L. M., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.01.035 · Cited by 189 · see citing works
“Although selective inhibitors to BRAF mutant proteins have been developed, their effectiveness is limited by the frequent emergence of resistance (Brighton et al., 2018; Fedele et al., 2018; Martz et al., 2014).”
Ramesh, A., Kumar, S., Nandi, D., & Kulkarni, A. A. (2019) · Advanced Materials · doi:10.1002/adma.201904364 · Cited by 191 · see citing works
MEK inhibitor resistance mechanisms and recent developments in combination trials
Kun, E., Tsang, Y. T. M., Ng, C. W., Gershenson, D. M., & Wong, K. (2020) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2020.102137 · Cited by 189 · see citing works
Mao, P., Cohen, O., Kowalski, K. J., Kusiel, J. G., Buendia-Buendia, J. E., Cuoco, M. S., Exman, P., Wander, S. A., Waks, A. G., Nayar, U., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-3958 · Cited by 172 · see citing works
Combinations with Allosteric SHP2 Inhibitor TNO155 to Block Receptor Tyrosine Kinase Signaling
Liu, C., Lu, H., Wang, H., Loo, A., Zhang, X., Yang, G., Kowal, C., Delach, S., Wang, Y., Goldoni, S., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-2718 · Cited by 167 · see citing works
“The efficacy of TNO155 plus ribociclib was also comparable with that of TNO155 plus trametinib, a synergistic combination in KRAS-mutant (21, 33) and RTK-driven cancers (42) but much less tolerated.”
BackgroundDrugging KRAS: Current perspectives and state-of-art review
Parikh, K., Banna, G., Liu, S. V., Friedlaender, A., Desai, A., Subbiah, V., & Addeo, A. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-022-01375-4 · Cited by 164 · see citing works
Insulin receptor endocytosis in the pathophysiology of insulin resistance
Hall, C., Yu, H., & Choi, E. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-0456-3 · Cited by 137 · see citing works
The biological underpinnings of therapeutic resistance in pancreatic cancerPreprint
Beatty, G. L., Werba, G., Lyssiotis, C. A., & Simeone, D. M. (2021) · Genes & Development · doi:10.1101/gad.348523.121 · Cited by 133 · see citing works
“mutant KRAS (Fedele et al. 2018), and SHP2 inhibitors are being explored in phase 1 clinical trials.”
BackgroundSelf-citationNew Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness
Yang, H., Liang, S.-Q., Schmid, R. A., & Peng, R.-W. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00953 · Cited by 129 · see citing works
“Recent studies in KRAS-mutant lung cancer (54, 55) and pancreatic adenocarcinoma (55), KRAS-amplified gastric carcinoma (56), and multiple other cancer models expressing mutant or wild-type KRAS (57, 58) revealed that the antitumor effect of MEK inhibitor treatment could be dramatically potentiated by concurrent SHP2…”
BackgroundModulation of the proteostasis network promotes tumor resistance to oncogenic KRAS inhibitors
Lv, X., Lu, X., Cao, J., Luo, Q., Ding, Y., Peng, F., Pataer, A., Lu, D., Han, D., Malmberg, E., et al. (2023) · Science · doi:10.1126/science.abn4180 · Cited by 123 · see citing works
Kerr, D. L., Haderk, F., & Bivona, T. G. (2021) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2020.11.007 · Cited by 124 · see citing works
Mechanisms of Resistance to KRASG12C Inhibitors
Dunnett-Kane, V., Nicola, P. A., Blackhall, F. H., & Lindsay, C. R. (2021) · Cancers · doi:10.3390/cancers13010151 · Cited by 120 · see citing works
“found that G12C/SHP2 inhibition increased CD8+ T cell infiltration into the tumour microenvironment, and triple therapy with PD-1 inhibitors resulted in greater tumour regression in PDAC murine models [60].”
BackgroundA comprehensive review of SHP2 and its role in cancer
Asmamaw, M. D., Shi, X.-J., Zhang, L.-R., & Liu, H.-M. (2022) · Cellular Oncology · doi:10.1007/s13402-022-00698-1 · Cited by 119 · see citing works
Brown, W. S., McDonald, P. C., Nemirovsky, O., Awrey, S., Chafe, S. C., Schaeffer, D. F., Li, J., Renouf, D. J., Stanger, B. Z., & Dedhar, S. (2020) · Cell Reports Medicine · doi:10.1016/j.xcrm.2020.100131 · Cited by 111 · see citing works
“However, a PDAC cell line, MIA PaCa-2, harbors a G12C mutation in KRAS and has been used in studies evaluating KRAS inhibitors.(7,14) We cultured MIA PaCa-2 cells with increasing concentrations of AMG 510 for 72 h and assessed the MEK-ERK and AKT signaling pathways.”
MethodTherapeutic targeting of RAS: New hope for drugging the “undruggable”
Khan, I., Rhett, J. M., & O’Bryan, J. P. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2019.118570 · Cited by 109 · see citing works
Sun, Y., Meyers, B. A., Czakó, B., Leonard, P. G., Mseeh, F., Harris, A. L., Wu, Q., Johnson, S. B., Parker, C. A., Cross, J. B., et al. (2020) · Cancer Research · doi:10.1158/0008-5472.can-20-1634 · Cited by 106 · see citing works
“Second, the clinical response toMEK inhibitors is limited by adaptive feedback activation through multiple RTKs (35, 38), therefore, combination of SHP2 inhibitor and MEK inhibitor has demonstrated antitumor efficacy in mice (8, 36).”
BackgroundVainonen, J. P., Momeny, M., & Westermarck, J. K. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abe2967 · Cited by 105 · see citing works
“Furthermore, combination with SHP099 allowed a decrease in the dose of the MEK inhibitor trametinib, preventing trametinib-associated side effects and resulting in enhanced efficacy in xenograft mouse models of several cancer types (43).”
BackgroundCombined Inhibition of SHP2 and CXCR1/2 Promotes Antitumor T-cell Response in NSCLC
Tang, K. H., Li, S., Khodadadi-Jamayran, A., Jen, J., Han, H., Guidry, K., Chen, T., Hao, Y., Fedele, C., Zebala, J. A., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0369 · Cited by 105 · see citing works
Self-citationTyrosyl phosphorylation of KRAS stalls GTPase cycle via alteration of switch I and II conformation
Kano, Y., Gebregiworgis, T., Marshall, C. B., Radulovich, N., Poon, B. P. K., St-Germain, J., Cook, J. D., Valencia-Sama, I., Grant, B. M. M., Herrera, S. G., et al. (2019) · Nature Communications · doi:10.1038/s41467-018-08115-8 · Cited by 103 · see citing works
Ozkan‐Dagliyan, I., Diehl, J. N., George, S. D., Schaefer, A., Papke, B., Klotz‐Noack, K., Waters, A. M., Goodwin, C. M., Gautam, P., Pierobon, M., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107764 · Cited by 102 · see citing works
“Recent studies showed that concurrent treatment with a SHP2 inhibitor can negate the RTK-mediated compensatory activities that are stimulated by ERK MAPK inhibition and can synergistically enhance MEKi activity (Ahmed et al., 2019; Fedele et al., 2018; Mainardi et al., 2018; Ruess et al., 2018; Wong et al., 2018).”
BackgroundTargeting KRAS in pancreatic cancer: new drugs on the horizon
Bannoura, S. F., Uddin, M. H., Nagasaka, M., Fazili, F., Hallak, M. N. A., Philip, P. A., El‐Rayes, B. F., & Azmi, A. S. (2021) · Cancer and Metastasis Reviews · doi:10.1007/s10555-021-09990-2 · Cited by 105 · see citing works
SHP2: A Pleiotropic Target at the Interface of Cancer and Its Microenvironment
Sodir, N. M., Pathria, G., Adamkewicz, J. I., Kelley, E. H., Sudhamsu, J., Merchant, M. A., Chiarle, R., & Maddalo, D. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-0383 · Cited by 103 · see citing works
“87) or the mutation P491Q (113) confer drug resistance by interfering with the docking of the drug into the target while keeping the enzyme catalytically active.”
BackgroundCombinatorial strategies to target RAS-driven cancers
Perurena, N., Situ, L., & Cichowski, K. M. (2024) · Nature reviews. Cancer · doi:10.1038/s41568-024-00679-6 · Cited by 104 · see citing works
Endothelial deletion of SHP2 suppresses tumor angiogenesis and promotes vascular normalization
Xu, Z., Guo, C., Ye, Q., Shi, Y., Sun, Y., Zhang, J., Huang, J., Huang, Y., Zeng, C., Zhang, X. Z., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26697-8 · Cited by 100 · see citing works
Strategies Targeting Protein Tyrosine Phosphatase SHP2 for Cancer Therapy
Song, Y., Wang, S., Zhao, M., Yang, X., & Yu, B. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c02008 · Cited by 100 · see citing works
KMT2D deficiency drives lung squamous cell carcinoma and hypersensitivity to RTK-RAS inhibition
Pan, Y., Han, H., Hu, H., Wang, H., Song, Y., Yuan, H., Tong, X., Patel, A. S., Misirlioğlu, S., Tang, S., et al. (2022) · Cancer Cell · doi:10.1016/j.ccell.2022.11.015 · Cited by 100 · see citing works
Quintana, E., Schulze, C. J., Myers, D. R., Choy, T. J., Mordec, K., Wildes, D. P., Shifrin, N. T., Belwafa, A., Koltun, E. S., Gill, A. L., et al. (2020) · Cancer Research · doi:10.1158/0008-5472.can-19-3038 · Cited by 98 · see citing works
“, MEK (6), KRAS (61), or RTK (62) inhibitors] or extraproliferative functions of RAS (e.”
BackgroundInfluentialLu, H., Liu, C., Velazquez, R., Wang, H., Dunkl, L. M., Kazic-Legueux, M., Haberkorn, A., Billy, E., Manchado, E., Brachmann, S. M., et al. (2019) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-18-0852 · Cited by 90 · see citing works
“Fedele and colleagues (55) also reported the combinationbenefits of SHP2 and MEK inhibition in KRAS-mutant cancer models as well as KRAS WT breast and ovarian cancer models but on the Lu et al.”
BackgroundSynthetic Lethal Interaction of SHOC2 Depletion with MEK Inhibition in RAS-Driven Cancers
Sulahian, R., Kwon, J. J., Walsh, K. H., Pailler, E., Bosse, T. L., Thaker, M., Almanza, D., Dempster, J. M., Pan, J., Piccioni, F., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.08.090 · Cited by 90 · see citing works
“The phenomenon of cancer cells exhibiting compensatory upregulation of multiple RTKs in response to MAPK inhibition motivated the rationale in targeting SHP2, a ubiquitous node downstream of multiple RTK signaling pathways, in combination with various MAPK inhibitors to prevent RTK-mediated adaptive resistance (Fedele…”
BackgroundLeung, C. O. N., Tong, M., Chung, K. P. S., Zhou, L., Che, N., Tang, K. H., Ding, J., Lau, E. Y.-T., Ng, I. O., Ma, S., et al. (2019) · Hepatology · doi:10.1002/hep.30989 · Cited by 88 · see citing works
“167 pancreatic ductal adenocarcinoma (PDAC) and anaplastic lymphoma kinase mutant non-small-cell lung cancer cells.(16,31) In addition to the enhanced apoptotic effect, we found that the SHP099/sorafenib combination led to the senescence of HCC cells.”
BackgroundResultInfluentialSelf-citationMechanisms of resistance to tyrosine kinase inhibitor‐targeted therapy and overcoming strategies
Ou, X., Gao, G., Habaz, I. A., & Wang, Y. (2024) · MedComm · doi:10.1002/mco2.694 · Cited by 93 · see citing works
“244 245–248 Therefore, SHP2 inhibitors as part of combination therapy may significantly enhance the therapeutic effects of RTK, RAS, and MAPK pathway inhibitors (e.g., EGFR-TKIs, KRAS G12C -TKIs).”
BackgroundADAM17: An Emerging Therapeutic Target for Lung Cancer
Saad, M. I., Rose‐John, S., & Jenkins, B. J. (2019) · Cancers · doi:10.3390/cancers11091218 · Cited by 80 · see citing works
Comprehensive Analysis of ERK1/2 Substrates for Potential Combination Immunotherapies
Yang, L., Zheng, L., Chng, W. J., & Ding, J. L. (2019) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2019.09.005 · Cited by 76 · see citing works
“The combination of SHP2 inhibition and MEK1/2 inhibitor, trametinib, is highly efficacious in multiple cancer models, regardless of KRAS mutations [72].”
BackgroundUnderstanding Drug Sensitivity and Tackling Resistance in Cancer
Tyner, J. W., Haderk, F., Kumaraswamy, A., Baughn, L. B., Ness, B. V., Liu, S., Marathe, H., Alumkal, J. J., Bivona, T. G., Chan, K. S., et al. (2022) · Cancer Research · doi:10.1158/0008-5472.can-21-3695 · Cited by 77 · see citing works
“Similarly, drug efficacy can be nullified by rapid feedback activation of oncogenic signaling, as exemplified by the limited treatment response of KRAS-mutant tumors to single-agent KRAS (37) or MEK inhibitors (38) or of estrogen receptor–positive breast cancer to single-agent PI3K inhibition (39).”
BackgroundDrilon, A. E. D. C., Sharma, M. R., Johnson, M. L., Yap, T. A., Gadgeel, S. M., Nepert, D. L., Feng, G., Reddy, M. B., Harney, A. S., Elsayed, M., et al. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-0361 · Cited by 75 · see citing works
“The inhibitor-bound SHP2 protein complex was prepared by mixing purified SHP2(1-525) with a 5-fold molar excess of PF-07282892 (in DMSO) and incubated on ice for at least 30 minutes.”
InfluentialYu, C., Luo, D., Yu, J., Zhang, M., Zheng, X., Xu, G., Wang, J., Wang, H., Xu, Y., Jiang, K., et al. (2022) · Oncogene · doi:10.1038/s41388-021-02077-w · Cited by 70 · see citing works
“Indeed, the heterogeneity of RTK/RTK ligand activation renders combination therapies with MAPKi and RTKi unfeasible [33].”
BackgroundTargeting RAS Mutant Colorectal Cancer with Dual Inhibition of MEK and CDK4/6
Sorokin, A. V., Marie, P. K., Bitner, L., Syed, M., Woods, M. N., Manyam, G. C., Kwong, L. N., Johnson, B., Morris, V. K., JONES, P. G., et al. (2022) · Cancer Research · doi:10.1158/0008-5472.can-22-0198 · Cited by 74 · see citing works
Creating MHC-Restricted Neoantigens with Covalent Inhibitors That Can Be Targeted by Immune Therapy
Hattori, T., Maso, L., Araki, K. Y., Koide, A., Hayman, J., Akkapeddi, P., Bang, I., Neel, B. G., & Koide, S. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-1074 · Cited by 72 · see citing works
“NCI-H358, NCI-H522, NCI-H1650, and SW1573 cells were obtained as described previously (62).”
Self-citationDrugging the Undruggable: Advances on RAS Targeting in Cancer
Molina‐Arcas, M., Samani, A., & Downward, J. (2021) · Genes · doi:10.3390/genes12060899 · Cited by 73 · see citing works
“SHP2 inhibitors also prevent adaptative resistance to MEK inhibitors and combinations of MEK plus SHP2 inhibitors produce tumour regression in several RAS-driven tumours [67].”
BackgroundWang, J., Pollard, K., Allen, A. N., Tomar, T., Pijnenburg, D., Yao, Z., Rodríguez, F. J., & Pratilas, C. A. (2020) · Cancer Research · doi:10.1158/0008-5472.can-20-1365 · Cited by 70 · see citing works
Rocca, A., Braga, L., Volpe, M. C., Maiocchi, S., & Generali, D. (2022) · Cancers · doi:10.3390/cancers14215306 · Cited by 65 · see citing works
SHP2 is a multifunctional therapeutic target in drug resistant metastatic breast cancer
Chen, H., Libring, S., Ruddraraju, K. V., Miao, J., Solorio, L., Zhang, Z., & Wendt, M. K. (2020) · Oncogene · doi:10.1038/s41388-020-01488-5 · Cited by 64 · see citing works
Valencia-Sama, I., Ladumor, Y., Kee, L., Adderley, T., Christopher, G., Robinson, C. M., Kano, Y., Ohh, M., & Irwin, M. S. (2020) · Cancer Research · doi:10.1158/0008-5472.can-19-3822 · Cited by 62 · see citing works
Strategies to overcome drug resistance using SHP2 inhibitors
Liu, M., Gao, S., Elhassan, R. M., Hou, X., & Fang, H. (2021) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.03.037 · Cited by 59 · see citing works
Middleton, G., Robbins, H. L., André, F., & Swanton, C. (2021) · Annals of Oncology · doi:10.1016/j.annonc.2021.11.004 · Cited by 58 · see citing works
Tumor Intrinsic Efficacy by SHP2 and RTK Inhibitors in KRAS-Mutant Cancers
Hao, H.-X., Wang, H., Liu, C., Kovats, S., Velazquez, R., Lu, H., Pant, B., Shirley, M., Meyer, M. J., Pu, M., et al. (2019) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-19-0170 · Cited by 53 · see citing works
New strategies for targeting kinase networks in cancer
Yesilkanal, A. E., Johnson, G. L., Ramos, A. F., & Rosner, M. R. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101128 · Cited by 55 · see citing works
“SHP099, and inhibitor of the SHP2 (Src homology region 2-containing protein tyrosine phosphatase 2) tyrosine phosphatase, revealed that SHP2 is required for receptor tyrosine kinase receptor activation of RAS proteins and activation of the MAPK pathway upon KRAS G12C targeting (51).”
BackgroundA mechanism for hypoxia-induced inflammatory cell death in cancer
Bhardwaj, A., Panepinto, M. C., Ueberheide, B. M., & Neel, B. G. (2024) · Nature · doi:10.1038/s41586-024-08136-y · Cited by 60 · see citing works
“Sources of the cell lines used here (except for KATO III, SNU 16 and FaDu) have previously been described 40,41 ; following their original direct purchase from ATCC or STR validation, lines were maintained as frozen stocks by the Neel Laboratory.”
Self-citationBurns, T. F., Borghaei, H., Ramalingam, S. S., Mok, T. S. K., & Peters, S. (2020) · Journal of Clinical Oncology · doi:10.1200/jco.20.00744 · Cited by 56 · see citing works
“Furthermore,MEK inhibitors andSHP2 inhibitorswere found to be synergistic in KRAS-mutant cancer cell lines, including NSCLC lines, making this combination also worthy of additional exploration.(92,112,113) The SHP2 inhibitors, TNO155 (Novartis) and RMC-4630 (Revolution Medicine), are currently in active phase I/II cli…”
BackgroundA proteomic and phosphoproteomic landscape of KRAS mutant cancers identifies combination therapies
Liu, Z., Liu, Y., Qian, L., Jiang, S., Gai, X., Ye, S., Chen, Y., Wang, X., Zhai, L., Xu, J. Q., et al. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.07.021 · Cited by 54 · see citing works
Parkin, A., Man, J., Timpson, P., & Pajic, M. (2019) · FEBS Journal · doi:10.1111/febs.15011 · Cited by 52 · see citing works
Targeting KRAS mutations: orchestrating cancer evolution and therapeutic challenges
Choucair, K., Imtiaz, H., Uddin, M. H., Nagasaka, M., Al-Hallak, M. N., Philip, P. A., El-Rayes, B., Pasche, B., & Azmi, A. S. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02473-8 · Cited by 57 · see citing works
Tyrosine phosphatases regulate resistance to ALK inhibitors in ALK+ anaplastic large cell lymphoma
Atabay, E. K., Mecca, C., Wang, Q., Ambrogio, C., Mota, I. A., Prokoph, N., Mura, G., Martinengo, C., Patrucco, E., Leonardi, G. C., et al. (2021) · Blood · doi:10.1182/blood.2020008136 · Cited by 51 · see citing works
Chen, W. S., Liang, Y., Zong, M., Liu, J. J., Kaneko, K., Hanley, K. L., Zhang, K., & Feng, G.-S. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109974 · Cited by 50 · see citing works
“(Ahmed et al., 2019; Dardaei et al., 2018; Fedele et al., 2018; Mainardi et al., 2018; Ruess et al., 2018; Wong et al., 2018), making Shp2 an attractive drug target.”
Gebregiworgis, T., Kano, Y., St-Germain, J., Radulovich, N., Udaskin, M. L., Mentes, A., Huang, R., Poon, B. P. K., He, W., Valencia-Sama, I., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26526-y · Cited by 49 · see citing works
“RAS/RAF binding was assessed using the RAS activation assay kit from Millipore (17-218).”
MethodAvery, T. Y., Köhler, N., Zeiser, R., Brummer, T., & Ruess, D. A. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.931774 · Cited by 51 · see citing works
Structural impact of GTP binding on downstream KRAS signaling
Menyhárd, D. K., Pálfy, G., Orgován, Z., Vida, I., Keserű, G. M., & Perczel, A. (2020) · Chemical Science · doi:10.1039/d0sc03441j · Cited by 50 · see citing works
Targeting Glucose Metabolism Sensitizes Pancreatic Cancer to MEK Inhibition
Yan, L., Tu, B., Yao, J., Gong, J., Carugo, A., Bristow, C. A., Wang, Q., Zhu, C., Dai, B., Kang, Y., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-3792 · Cited by 48 · see citing works
“Previous studies have identified 434 reactivation of multiple RTKs as a prominent mechanism of adaptive resistance to MEK 435 inhibition in KRAS-driven tumors (13,33,35).”
BackgroundTargeting KRAS mutant lung cancer: light at the end of the tunnel
Drosten, M., & Barbacid, M. (2021) · Molecular Oncology · doi:10.1002/1878-0261.13168 · Cited by 47 · see citing works
“SHP2 is thought to act upstream of the RAS GEFs SOS1/SOS2, and its inhibition may facilitate inactivation of mutant KRAS [65].”
BackgroundThe role of wild-type RAS in oncogenic RAS transformation
Sheffels, E., & Kortum, R. L. (2021) · Genes · doi:10.3390/genes12050662 · Cited by 42 · see citing works
Recent advances in the discovery of protein tyrosine phosphatase SHP2 inhibitors
Kong, J., & Long, Y. (2022) · RSC Medicinal Chemistry · doi:10.1039/d1md00386k · Cited by 45 · see citing works
Lu, H., Liu, C., Huynh, H. T., Le, T. B. U., LaMarche, M. J., Mohseni, M., Engelman, J. A., Hammerman, P. S., Caponigro, G., & Hao, H.-X. (2020) · Oncotarget · doi:10.18632/oncotarget.27435 · Cited by 45 · see citing works
“To further investigate whether this SHP2 inhibitorresistant rapid feedback activation of SHP2 by FGFRs is a unique phenomenon due to the binding of allosteric inhibitors to SHP2 or a general effect due to ERK inhibition, we used the MEK inhibitor selumetinib to trigger the pathway feedback activation as previously des…”
MethodSmall Molecule KRAS Inhibitors: The Future for Targeted Pancreatic Cancer Therapy?
Gillson, J., Ramaswamy, Y., Singh, G., Gorfe, A. A., Pavlakis, N., Samra, J. S., Mittal, A., & Sahni, S. (2020) · Cancers · doi:10.3390/cancers12051341 · Cited by 45 · see citing works
Lietman, C. D., Johnson, M. L., McCormick, F., & Lindsay, C. R. (2022) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_351333 · Cited by 44 · see citing works
Marsh-Armstrong, B. P., Fajnzylber, J. M., Korntner, S., Plaman, B. A., & Bishop, A. C. (2018) · ACS Omega · doi:10.1021/acsomega.8b02200 · Cited by 44 · see citing works
Karachaliou, N., Cardona, A. F., Bracht, J. W. P., Aldeguer, E., Drozdowskyj, A., Fernández-Bruno, M., CHAIB-OUKADOUR, I., Berenguer, J., Santarpía, M., Ito, M., et al. (2018) · EBioMedicine · doi:10.1016/j.ebiom.2018.11.036 · Cited by 43 · see citing works
“SHP2 has a role in stimulating MAPK signaling, downstream of various growth factors [30,31].”
BackgroundZhao, B., Dierichs, L., Gu, J., Trajkovic‐Arsic, M., Hilger, R. A., Savvatakis, K., Vega-Rubín-de-Celis, S., Liffers, S., Peña‐Llopis, S., Behrens, D., et al. (2020) · Cell Death Discovery · doi:10.1038/s41420-020-0246-7 · Cited by 42 · see citing works
Adamopoulos, C., Cave, D. D., & Papavassiliou, A. G. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25031631 · Cited by 41 · see citing works
“In addition, several studies demonstrated that SHP2 inhibition prevents the receptor tyrosine kinase (RTK)-mediated development of adaptive resistance caused by MEK or BRAF inhibitors [53,54].”
BackgroundThe role of CRAF in cancer progression: from molecular mechanisms to precision therapies
Riaud, M., Maxwell, J., Soria‐Bretones, I., Dankner, M., Li, M., & Rose, A. A. N. (2024) · Nature reviews. Cancer · doi:10.1038/s41568-023-00650-x · Cited by 39 · see citing works
“As discussed earlier, CRAF mutants with high-kinase activity signal predominantly as dimers, and therefore, therapies that prevent RAF dimerization (RTK or SHP2 inhibitors) in RAS wild-type tumours could be coupled with downstream pan-RAF or MEK inhibitors 196 .”
Molecular Insights on Signaling Cascades in Breast Cancer: A Comprehensive Review
Panda, V. K., Mishra, B., Mahapatra, S., Swain, B., Malhotra, D., Saha, S., Khanra, S., Mishra, P., Majhi, S., Kumari, K., et al. (2025) · Cancers · doi:10.3390/cancers17020234 · Cited by 40 · see citing works
“It exhibited synergistic effects across various cell lines, impeding reactivation of ERK in response to MEK inhibitors and hindering transcriptional activation [250].”
The sixth international RASopathies symposium: Precision medicine—From promise to practice
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“This reactivation is blocked by SHP099, an allosteric SHP2 inhibitor that prevents RASexchange, thereby decreasing RAS-GTP loading for wild-type RAS and “cycling RAS mutants,” such as KRAS-G12C (Fedele et al., 2018).”
Self-citationAn allosteric interaction controls the activation mechanism of SHP2 tyrosine phosphatase
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Shipping out MEK inhibitor resistance with SHP2 inhibitors
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Targeting farnesylation as a novel therapeutic approach in HRAS-mutant rhabdomyosarcoma
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“Therefore, SHP2 represents a promising target, and inhibition of SHP2 can target a point of convergence from upstream RTK signaling and, together with inhibition of RAS effector pathways, provide an enhanced antitumor effect ( 11 , 22 , 26 , 28 , 29 ).”
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- 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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