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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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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
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
“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 76
“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 72
Rocca, A., Braga, L., Volpe, M. C., Maiocchi, S., & Generali, D. (2022) · Cancers · doi:10.3390/cancers14215306 · Cited by 71
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
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
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 58
Middleton, G., Robbins, H. L., André, F., & Swanton, C. (2021) · Annals of Oncology · doi:10.1016/j.annonc.2021.11.004 · Cited by 59
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
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 58
“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
“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 58
“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 55
Parkin, A., Man, J., Timpson, P., & Pajic, M. (2019) · FEBS Journal · doi:10.1111/febs.15011 · Cited by 54
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 67
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 52
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
“(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
“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
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
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
“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 49
“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
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
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
“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
More to the RAS Story: KRAS G12C Inhibition, Resistance Mechanisms, and Moving Beyond KRAS G12C
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
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
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
“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
Adamopoulos, C., Cave, D. D., & Papavassiliou, A. G. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25031631 · Cited by 43
“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 40
“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 47
“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
Gripp, K. W., Schill, L., Schoyer, L., Stronach, B. E., Bennett, A. M., Blasér, S., Brown, A., Burdine, R. D., Burkitt‐Wright, E., Castel, P., et al. (2019) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.61434 · Cited by 40
“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
Anselmi, M., & Hub, J. S. (2020) · Scientific Reports · doi:10.1038/s41598-020-75409-7 · Cited by 39
Campbell, B. B., Galati, M. A., Stone, S. C., Riemenschneider, A. N., Edwards, M., Sudhaman, S., Siddaway, R., Komosa, M., Nunes, N. M., Nobre, L. F., et al. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1050 · Cited by 40
Shipping out MEK inhibitor resistance with SHP2 inhibitors
Torres-Ayuso, P., & Brognard, J. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-0915 · Cited by 37
Targeting farnesylation as a novel therapeutic approach in HRAS-mutant rhabdomyosarcoma
Odeniyide, P., Yohe, M. E., Pollard, K., Vaseva, A. V., Calizo, A., Zhang, L., Rodríguez, F. J., Gross, J. M., Allen, A. N., Wan, X., et al. (2022) · Oncogene · doi:10.1038/s41388-022-02305-x · Cited by 38
Cell-Intrinsic Mechanisms of Drug Tolerance to Systemic Therapies in Cancer
Léonce, C., Saintigny, P., & Ortiz‐Cuaran, S. (2021) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-21-0038 · Cited by 41
Prevention and Reversion of Pancreatic Tumorigenesis through a Differentiation-Based Mechanism
Krah, N. M., Narayanan, S. M., Yugawa, D. E., Straley, J. A., Wright, C. V. E., MacDonald, R. J., & Murtaugh, L. C. (2019) · Developmental Cell · doi:10.1016/j.devcel.2019.07.012 · Cited by 41
A New View of Activating Mutations in Cancer
Nussinov, R., Tsai, C., & Jang, H. (2022) · Cancer Research · doi:10.1158/0008-5472.can-22-2125 · Cited by 36
Targeting Mutant KRAS in Pancreatic Cancer: Futile or Promising?
Nollmann, F. I., & Ruess, D. A. (2020) · Biomedicines · doi:10.3390/biomedicines8080281 · Cited by 33
Targeting KRAS in PDAC: A New Way to Cure It?
He, Q., Liu, Z., & Wang, J. (2022) · Cancers · doi:10.3390/cancers14204982 · Cited by 39
Kim, S. S., Carvajal, R. D., Kim, M., & Yang, H. W. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112570 · Cited by 35
Wang, J., Calizo, A., Zhang, L., Pino, J. C., Lyu, Y., Pollard, K., Zhang, X., Larsson, A. T., Conniff, E., Llosa, N. J., et al. (2023) · Science Advances · doi:10.1126/sciadv.adg8876 · Cited by 33
“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 ).”
BackgroundTargeting PDGFRα-activated glioblastoma through specific inhibition of SHP-2–mediated signaling
Sang, Y., Hou, Y., Cheng, R., Zheng, L., Alvarez, A. A., Hu, B., Cheng, S., Zhang, W., Li, Y., & Feng, H. (2019) · Neuro-Oncology · doi:10.1093/neuonc/noz107 · Cited by 36
Liu, S., Zou, Q., Chen, J., Yao, X., Guan, P., Liang, W., Deng, P., Lai, X., Yin, J., Chen, J., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci145035 · Cited by 33
“Despite the clinical effectiveness of MEK inhibitors, their clinical utilization has shown limited success owing to the rapid development of resistance (18, 19).”
BackgroundFerrous iron–activatable drug conjugate achieves potent MAPK blockade in KRAS -driven tumors
Jiang, H., Muir, R. K., Gonciarz, R. L., Olshen, A. B., Yeh, I., Hann, B. C., Zhao, N., Wang, Y.-H., Behr, S. C., Korkola, J. E., et al. (2022) · Journal of Experimental Medicine · doi:10.1084/jem.20210739 · Cited by 33
Dampening oncogenic RAS signaling
Bivona, T. G. (2019) · Science · doi:10.1126/science.aav6703 · Cited by 33
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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