TEAD Inhibitors Sensitize KRASG12C Inhibitors via Dual Cell Cycle Arrest in KRASG12C-Mutant NSCLC
Open accessAbstract
KRASG12C is one of the most common mutations detected in non-small cell lung cancer (NSCLC) patients, and it is a marker of poor prognosis. The first FDA-approved KRASG12C inhibitors, sotorasib and adagrasib, have been an enormous breakthrough for patients with KRASG12C mutant NSCLC; however, resistance to therapy is emerging. The transcriptional coactivators YAP1/TAZ and the family of transcription factors TEAD1-4 are the downstream effectors of the Hippo pathway and regulate essential cellular processes such as cell proliferation and cell survival. YAP1/TAZ-TEAD activity has further been implicated as a mechanism of resistance to targeted therapies. Here, we investigate the effect of combining TEAD inhibitors with KRASG12C inhibitors in KRASG12C mutant NSCLC tumor models. We show that TEAD inhibitors, while being inactive as single agents in KRASG12C-driven NSCLC cells, enhance KRASG12C inhibitor-mediated anti-tumor efficacy in vitro and in vivo. Mechanistically, the dual inhibition of KRASG12C and TEAD results in the downregulation of MYC and E2F signatures and in the alteration of the G2/M checkpoint, converging in an increase in G1 and a decrease in G2/M cell cycle phases. Our data suggest that the co-inhibition of KRASG12C and TEAD leads to a specific dual cell cycle arrest in KRASG12C NSCLC cells.
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Combination therapies with TEAD inhibitors synergize with KRAS inhibitors by blocking the cell cycle.
“Combination therapies with TEAD inhibitors synergize with KRAS inhibitors by blocking the cell cycle [127].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [127]
The Conclusions and Discussion report that adding a TEAD inhibitor potentiated KRASG12C inhibition and produced combination-specific cell-cycle arrest. The claim generalizes this finding to KRAS inhibitors broadly, whereas the study tested KRASG12C inhibitors in KRASG12C-mutant NSCLC models. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCombining inhibitors of TEAD proteins with KRASi prevents feedback reactivation.
“An alternative preclinical strategy being tested is combining inhibitors of TEAD proteins with KRASi, preventing feedback reactivation [125,127].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [127]
The Introduction describes testing TEAD inhibitors with KRASG12C inhibitors, and the Conclusions report enhanced effects in NSCLC cell lines. The paper attributes the combination’s effect to cell-cycle changes; the passages do not show that it prevents feedback reactivation. (LLM, conf=0.86)
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- Authors
- Tammaccaro, S. L., Prigent, P., Le Bail, J.-C., Dos-Santos, O., Dassencourt, L., Eskandar, M., Buzy, A., Venier, O., Guillemot, J.-C., Veeranagouda, Y., Didier, M., Spanakis, E., Kanno, T., Cesaroni, M., Mathieu, S., Canard, L., Casse, A., Windenberger, F., Calvet, L., Noblet, L., Sidhu, S., Debussche, L., Moll, J., & Valtingojer, I.
- Affiliations
- Sanofi (France) (FR)
- Oncology, Sanofi R&D, 94400 Vitry-sur-Seine, France
- Molecular & Digital Histopathology, Sanofi R&D, 94400 Vitry-sur-Seine, France
- Corresponding author
- Tammaccaro, Salvina Laura
- Valtingojer, Iris
- ORCID
- Venue
- Pharmaceuticals
- Publisher
- MDPI AG
- Published
- 2023-04-06
- Volume
- 16
- Issue
- 4
- Pages
- 553
- ISSN
- 1424-8247 (ISSN-L)
- PMC
- PMC10142471
- OpenAlex
- W4362668006
- Cited by
- 18
- References
- 39
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 10 · 2023: 1
- FWCI
- 2.60
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Pharmaceuticals (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Sanofi
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- KRAS G12C, TEAD inhibitors, non-small cell lung cancer, sotorasib, adagrasib, Hippo signaling pathway, drug resistance, combination therapy, cell cycle arrest, G2/M checkpoint, c-Myc, E2F transcription factors, targeted therapy
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