The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies
Open accessAbstract
Resistance to RAF- and MEK-targeted therapy is a major clinical challenge. RAF and MEK inhibitors are initially but only transiently effective in some but not all patients with BRAF gene mutation and are largely ineffective in those with RAS gene mutation because of resistance. Through a genetic screen in BRAF-mutant tumor cells, we show that the Hippo pathway effector YAP (encoded by YAP1) acts as a parallel survival input to promote resistance to RAF and MEK inhibitor therapy. Combined YAP and RAF or MEK inhibition was synthetically lethal not only in several BRAF-mutant tumor types but also in RAS-mutant tumors. Increased YAP in tumors harboring BRAF V600E was a biomarker of worse initial response to RAF and MEK inhibition in patients, establishing the clinical relevance of our findings. Our data identify YAP as a new mechanism of resistance to RAF- and MEK-targeted therapy. The findings unveil the synthetic lethality of combined suppression of YAP and RAF or MEK as a promising strategy to enhance treatment response and patient survival.
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YAP/TAZ plays a crucial role in intrinsic and acquired resistance to inhibitors targeting the RTK/MAPK pathway.
“Particularly, YAP/TAZ plays a crucial role in the intrinsic and acquired resistance to inhibitors targeting RTK/MAPK pathway (24, 28–32).”
From YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis (2024) · cites this paper as [24]
The paper reports that YAP1 suppression overcame intrinsic resistance to RAF and MEK inhibitors, and that TAZ overexpression reduced sensitivity to those drugs (Abstract; page not available in our copy). It also found increased YAP in a small subset of paired tumors at acquired resistance, but describes this as suggesting a possible contribution rather than establishing a crucial role. The evidence does not extend to RTK-targeted inhibitors generally or establish TAZ's role in acquired resistance. (LLM, conf=0.87)
Experimental — accuracy not yet measuredDysregulation of the Hippo-YAP/TAZ pathway is a central resistance mechanism in various tumors to multiple targeted therapies, chemotherapies, hormonal therapies, and immunotherapies.
“Emerging evidence suggests that dysregulation of the Hippo-YAP/TAZ pathway is a central resistance mechanism in various tumors to multiple targeted therapies, chemotherapies, hormonal therapies, and immunotherapies (23–27).”
From YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis (2024) · cites this paper as [24]
The paper’s Abstract (page not provided) identifies YAP as a resistance mechanism for RAF- and MEK-targeted therapies across several BRAF- and RAS-mutant tumor types, and reports that TAZ overexpression reduced sensitivity to those inhibitors in one cell line. It does not establish resistance to chemotherapies, hormonal therapies, or immunotherapies, so it supports only the targeted-therapy portion of the citing sentence. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDysregulation of the Hippo-YAP/TAZ pathway serves as a central resistance mechanism in multiple therapies, particularly intrinsic and acquired resistance to RTK, RAF, or MEK inhibitors.
“accumulating evidence suggests that the dysregulation of the Hippo-YAP/TAZ pathway serves as a central resistance mechanism in multiple therapies, particularly in the intrinsic and acquired resistance to RTK, RAF, or MEK inhibitors (24, 28, 29).”
From YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis (2024) · cites this paper as [24]
The paper’s Abstract reports that YAP promotes resistance to RAF and MEK inhibitors, including intrinsic resistance in BRAF-mutant tumor models. It also reports increased YAP at acquired resistance in a small subset of paired melanoma samples, but describes that finding as suggestive. The passages do not establish resistance to RTK inhibitors or a central mechanism across multiple therapies. (LLM, conf=0.88)
Experimental — accuracy not yet measuredYAP1 is one of the major drivers of bypassing oncogene addiction and promoting acquired resistance to targeted therapies in several cancer types.
“The YAP1 oncogene has been well established as one of the major drivers of bypassing oncogene addiction and promoting acquired resistance to targeted therapies in several cancer types, including pancreatic cancer, lung cancer, colorectal cancer, melanoma, and glioblastoma.9,10,38,39,40”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [39]
The paper reports that YAP promotes resistance to RAF and MEK inhibitors in lung, melanoma, colorectal and pancreatic cancer models (Abstract; page unavailable). It also reports increased YAP in paired melanoma samples at acquired resistance, but describes that finding as suggestive rather than establishing YAP as a major driver of acquired resistance across cancer types. The copy does not establish the claim for glioblastoma. (LLM, conf=0.87)
Experimental — accuracy not yet measuredYAP is known to serve as a parallel survival effector when RAF or MEK is inhibited.
“YAP is known to serve as a parallel survival effector when RAF or MEK is inhibited [102].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [102]
Adaptive resistance, in which the inhibited pathway is reactivated due to induction of RTKs/RTK ligand genes, is a common form of intrinsic resistance.
“Adaptive resistance (termed “rebound” by some investigators), in which the inhibited pathway is reactivated due to induction of RTKs/RTK ligand genes, is a common form of intrinsic resistance (Anderson et al., 2017; Duncan et al., 2012; Lin et al., 2015; Manchado et al., 2016; Nazarian et al., 2010; Sun et al., 2014; Zawistowski et al., 2017).”
From SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling (2021) · cites this paper as Lin et al., 2015
YAP activity is positively correlated with resistance to therapies targeting KRAS signaling components including RAF and MEK.
“On the one hand, it is known that YAP activity is positively correlated with the resistance to therapies targeting KRAS signaling components including RAF and MEK,[ 28, 46 ] and YAP is required for KRAS‐dependent cell transformation: extracellular supplementation of YAP activators can rescue cancer cell killing after KRAS knockdown.[ 47 ]”
From Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK–YAP Signaling (2021) · cites this paper as [28]
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The Hippo Signaling Pathway in Drug Resistance in Cancer
Zeng, R., & Dong, J. (2021) · Cancers · doi:10.3390/cancers13020318 · Cited by 89 · see citing works
Overcoming Resistance to Dual Innate Immune and MEK Inhibition Downstream of KRAS
Kitajima, S., Asahina, H., Chen, T., Guo, S., Quiceno, L. G., Cavanaugh, J. D., Merlino, A. A., Tange, S., Terai, H., Kim, J. W., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.08.009 · Cited by 75 · see citing works
YAP1 oncogene is a context-specific driver for pancreatic ductal adenocarcinoma
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The Hippo pathway modulates resistance to BET proteins inhibitors in lung cancer cells
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Genome-wide CRISPR screening reveals genetic modifiers of mutant EGFR dependence in human NSCLC
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YAP/TAZ signalling in colorectal cancer: lessons from consensus molecular subtypes
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Yap1 Mediates Trametinib Resistance in Head and Neck Squamous Cell Carcinomas
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“Particularly, YAP/TAZ plays a crucial role in the intrinsic and acquired resistance to inhibitors targeting RTK/ MAPK pathway (24, 28–32).”
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Non-genetic adaptive resistance to KRASG12C inhibition: EMT is not the only culprit
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Differential Response and Resistance to KRAS-Targeted Therapy
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“YAP is known to serve as a parallel survival effector when RAF or MEK is inhibited [105].”
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- Authors
- Lin, L., Sabnis, A. J., Chan, E., Olivas, V., Cade, L., Pazarentzos, E., Asthana, S., Neel, D., Yan, J. J., Lu, X., Pham, L., Wang, M. M., Karachaliou, N., Cao, M. G., Manzano, J. L., Ramirez, J. L., Torres, J. M. S., Buttitta, F., Rudin, C. M., Collisson, E. A., Algazi, A., Robinson, E., Osman, I., Muñoz-Couselo, E., Cortes, J., Frederick, D. T., Cooper, Z. A., McMahon, M., Marchetti, A., Rosell, R., Flaherty, K. T., Wargo, J. A., & Bivona, T. G.
- Affiliations
- University of California, San Francisco (US)
- Institut Català d'Oncologia (ES)
- Hospital Universitario de La Princesa (ES)
- University of Chieti-Pescara (IT)
- Memorial Sloan Kettering Cancer Center (US)
- New York University (US)
- Massachusetts General Hospital (US)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Bivona, Trever G
- ORCID
- Lin, Luping
- Sabnis, Amit J
- Pazarentzos, Evangelos
- Neel, Dana
- Yan, Jenny Jiacheng
- Lu, Xinyuan
- Karachaliou, Niki
- Torres, Jose Miguel Sanchez
- Rudin, Charles M
- Collisson, Eric A
- Algazi, Alain
- Robinson, Eric
- Osman, Iman
- Frederick, Dennie T
- Cooper, Zachary A
- McMahon, Martin
- Marchetti, Antonio
- Rosell, Rafael
- Flaherty, Keith T
- Wargo, Jennifer A
- Bivona, Trever G
- Venue
- Nature Genetics
- Published
- 2015-02-09
- Volume
- 47
- Issue
- 3
- Pages
- 250-256
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC4930244
- OpenAlex
- W2079015343
- Cited by
- 551
- References
- 39
- Citations by year
- 2026: 23 · 2025: 41 · 2024: 59 · 2023: 47 · 2022: 49 · 2021: 56 · 2020: 44 · 2019: 51 · 2018: 62 · 2017: 39 · 2016: 47 · 2015: 31
- FWCI
- 31.81
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (DP2CA174497, P30CA008748, R01CA131261, P01CA163222)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- 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
- YAP, Hippo signaling pathway, RAF inhibitors, MEK inhibitors, drug resistance, synthetic lethality, combination therapy, BRAF V600E mutation
- MeSH terms
- Hippo Signaling Pathway, YAP-Signaling Proteins, Animals, Female, Humans, Mutation, Phosphoproteins, Genes, ras, Transcription Factors, Biomarkers, Tumor, Mice, SCID, Mice, Inbred NOD, Protein Serine-Threonine Kinases, Drug Resistance, Neoplasm, HT29 Cells, MAP Kinase Kinase Kinases, MAP Kinase Signaling System, Cell Line, Tumor, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Adaptor Proteins, Signal Transducing, Mice, Gene Knockdown Techniques, HEK293 Cells, Molecular Targeted Therapy, Heterografts
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