TEAD Inhibition Overcomes YAP1/TAZ-Driven Primary and Acquired Resistance to KRASG12C Inhibitors
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Abstract
Primary/intrinsic and treatment-induced acquired resistance limit the initial response rate to and long-term efficacy of direct inhibitors of the KRASG12C mutant in cancer. To identify potential mechanisms of resistance, we applied a CRISPR/Cas9 loss-of-function screen and observed loss of multiple components of the Hippo tumor suppressor pathway, which acts to suppress YAP1/TAZ-regulated gene transcription. YAP1/TAZ activation impaired the antiproliferative and proapoptotic effects of KRASG12C inhibitor (G12Ci) treatment in KRASG12C-mutant cancer cell lines. Conversely, genetic suppression of YAP1/WWTR1 (TAZ) enhanced G12Ci sensitivity. YAP1/TAZ activity overcame KRAS dependency through two distinct TEAD transcription factor–dependent mechanisms, which phenocopy KRAS effector signaling. First, TEAD stimulated ERK-independent transcription of genes normally regulated by ERK (BIRC5, CDC20, ECT2, FOSL1, and MYC) to promote progression through the cell cycle. Second, TEAD caused activation of PI3K–AKT–mTOR signaling to overcome apoptosis. G12Ci treatment-induced acquired resistance was also caused by YAP1/TAZ-TEAD activation. Accordingly, concurrent treatment with pharmacologic inhibitors of TEAD synergistically enhanced KRASG12C inhibitor antitumor activity in vitro and prolonged tumor suppression in vivo. In summary, these observations reveal YAP1/TAZ-TEAD signaling as a crucial driver of primary and acquired resistance to KRAS inhibition and support the use of TEAD inhibitors to enhance the antitumor efficacy of KRAS-targeted therapies. Significance: YAP1/TAZ-TEAD activation compensates for loss of KRAS effector signaling, establishing a mechanistic basis for concurrent inhibition of TEAD to enhance the efficacy of KRASG12C-selective inhibitor treatment of KRASG12C-mutant cancers. See related commentary by Johnson and Haigis, p. 4005
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YAP1 is dispensable for maintaining advanced KRAS-driven tumors, which are primarily sustained by oncogenic KRAS.
“These findings align with accumulated evidence that YAP1 is dispensable for maintaining advanced KRAS-driven tumors, which are primarily sustained by oncogenic KRAS.41,42”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [42]
In the section on acquired resistance (page unavailable), combined YAP1/TAZ knockdown did not affect growth of parental MIA PaCa-2 cells, but it partially reduced growth of parental H358 cells. The paper thus supports limited YAP1/TAZ dependence in some KRAS G12C–mutant cell models, not a general claim that YAP1 is dispensable for maintaining advanced tumors; it also finds that resistant cells become YAP1/TAZ-dependent. (LLM, conf=0.82)
Experimental — accuracy not yet measuredCombining TEAD inhibitors may overcome KRAS inhibitor resistance.
“Combining TEAD inhibitors may overcome this KRAS inhibitor resistance [40].”
YAP/TAZ interact with oncogenic KRAS-mediated signaling and modulate the response to KRAS inhibition.
“Similarly, it has long been known that YAP/TAZ interact with oncogenic KRAS-mediated signaling and modulate the response to KRAS inhibition.”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [104]
YAP/TAZ overcame KRAS dependency through TEAD-dependent transcription programs that are normally regulated by ERK, serving as a bypass of ERK signaling.
“In this case, YAP/TAZ overcame KRAS dependency through TEAD-dependent transcription programs that are normally regulated by ERK, serving as a bypass of ERK signaling.”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [104]
A recent CRISPR/Cas9 screen identified loss of the Hippo pathway components and activation of YAP1/TAZ as a mediator of resistance to KRAS G12C inhibition in cancer cell lines.
“A recent CRISPR/Cas9 screen identified loss of the Hippo pathway components and activation of YAP1/TAZ as a mediator of resistance to KRAS G12C inhibition in cancer cell lines [104].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [104]
In YAP/TAZ-mediated resistance to KRAS G12C inhibitors, TEAD was found to activate PI3K/AKT/mTOR pathway to inhibit apoptosis.
“In YAP/TAZ-mediated resistance to KRAS G12C inhibitors, TEAD was found to activate PI3K/AKT/mTOR pathway to inhibit apoptosis [104].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [104]
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References 76 · Cited by 91
Research works printed but not linked: 4
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- Authors
- Edwards, A. C., Stalnecker, C. A., Jean Morales, A., Taylor, K. E., Klomp, J. E., Klomp, J. A., Waters, A. M., Sudhakar, N., Hallin, J., Tang, T. T., Olson, P., Post, L., Christensen, J. G., Cox, A. D., & Der, C. J.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- 3Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
- Mirati Therapeutics (United States) (US)
- 5Vivace Therapeutics, Inc., San Mateo, California.
- ORCID
- Venue
- Cancer Research
- Published
- 2023-11-07
- Volume
- 83
- Issue
- 24
- Pages
- 4112-4129
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC10821578
- OpenAlex
- W4388464749
- Cited by
- 91
- References
- 76
- Citations by year
- 2026: 32 · 2025: 37 · 2024: 20 · 2023: 2
- FWCI
- 13.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- Funders
- National Cancer Institute (R01CA42978, P50CA196510, P50CA257911, U01CA199235, P01CA203657, R35CA232113, F31CA275260, T32CA009156, F32CA232529, F32 CA239328, K99 CA276700)
- Pancreatic Cancer Action Network (22-WG-DERB)
- U.S. Department of Defense (W81XWH2110692)
- National Institute of General Medical Sciences (T32GM119999)
- American Cancer Society (PF-20-069, PF-18-061)
- 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 › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- KRAS G12C inhibitors, acquired drug resistance, primary resistance, TEAD transcription factors, Hippo signaling pathway, PI3K/AKT/mTOR pathway, cell cycle progression, apoptosis, TEAD inhibitors, combination therapy, KRAS-mutant cancer
- MeSH terms
- YAP-Signaling Proteins, TEA Domain Transcription Factors, Humans, Neoplasms, Transcription Factors, Trans-Activators, Proto-Oncogene Proteins p21(ras), Drug Resistance, Neoplasm, Phosphatidylinositol 3-Kinases, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing
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