FAK inhibition combined with the RAF-MEK clamp avutometinib overcomes resistance to targeted and immune therapies in BRAF V600E melanoma

Simone Lubrano; Rodolfo Daniel Cervantes-Villagrana; Farhoud Faraji; Sydney Ramirez; Kuniaki Sato; Sendi R Adame-Garcia; Adam Officer; Nadia Arang; Damiano C Rigiracciolo; Paola Y Anguiano Quiroz; Claudia Martini; YiYu Wang; Fleur M Ferguson; Antonietta Bacchiocchi; Ruth Halaban; Silvia Coma; Sheri L Holmen; Jonathan A Pachter; Andrew E Aplin; J Silvio Gutkind

doi:10.1016/j.ccell.2025.02.001

FAK inhibition combined with the RAF-MEK clamp avutometinib overcomes resistance to targeted and immune therapies in BRAF V600E melanoma

Cancer Cell. 2025 Mar 10;43(3):428-445.e6. doi: 10.1016/j.ccell.2025.02.001. Epub 2025 Feb 27.

Authors

Simone Lubrano¹, Rodolfo Daniel Cervantes-Villagrana², Farhoud Faraji³, Sydney Ramirez⁴, Kuniaki Sato², Sendi R Adame-Garcia², Adam Officer², Nadia Arang⁵, Damiano C Rigiracciolo⁴, Paola Y Anguiano Quiroz⁶, Claudia Martini⁷, YiYu Wang⁸, Fleur M Ferguson⁸, Antonietta Bacchiocchi⁹, Ruth Halaban⁹, Silvia Coma¹⁰, Sheri L Holmen¹¹, Jonathan A Pachter¹⁰, Andrew E Aplin¹², J Silvio Gutkind¹³

Affiliations

¹ Department of Pharmacy, University of Pisa, 56126 Pisa, Italy; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: lubrano.simone16@gmail.com.
² Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
³ Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Department of Otolaryngology - Head and Neck Surgery, UC San Diego Health, La Jolla, CA 92037, USA.
⁴ Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
⁵ Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA.
⁶ Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; John Muir College, University of California, San Diego, La Jolla, CA 92093, USA.
⁷ Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.
⁸ Department of Chemistry and Biochemistry and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA.
⁹ Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520, USA.
¹⁰ Verastem Oncology, Needham, MA 02494, USA.
¹¹ Department of Surgery, University of Utah Health Sciences Center, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
¹² Department of Pharmacology, Physiology and Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, US.
¹³ Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: sgutkind@health.ucsd.edu.

PMID: 40020669
PMCID: PMC11903146 (available on 2026-03-10)
DOI: 10.1016/j.ccell.2025.02.001

Abstract

Widespread BRAF mutations result in persistent RAS-RAF-MEK-ERK (MAPK) signaling in melanoma. BRAF (BRAFi) and MEK (MEKi) inhibitors are approved for BRAF V600E melanomas, including those progressing on immunotherapy; however, rapid resistance to these agents highlights the need for novel strategies. Here, transcriptome analysis of BRAF V600E melanomas from patients resistant to BRAFi and MEKi shows activation of focal adhesion signaling. Consistently, BRAFi, MEKi, and the RAF-MEK clamp avutometinib activate focal adhesion kinase (FAK) in melanoma cells. Mechanistically, inhibition of an MAPK-RhoE (RND3) feedback loop results in the adaptive activation of RhoA-FAK-AKT. In turn, FAK inhibitors (FAKi) exert potent pro-apoptotic activity when combined with MAPK pathway inhibition. FAKi plus avutometinib overcomes resistance in multiple models derived from BRAFi plus MEKi-resistant melanoma patients and immunotherapy-resistant syngeneic mouse models. These findings provide a rationale for the development of avutometinib in combination with FAKi for patients with BRAF V600E melanoma progressing on BRAFi plus MEKi or immunotherapy.

Keywords: BRAF; FAK; MAPK signaling; MEK; avutometinib; immunotherapy; melanoma; resistance; signal transduction; targeted therapies.

MeSH terms

Animals
Antineoplastic Combined Chemotherapy Protocols* / pharmacology
Apoptosis / drug effects
Cell Line, Tumor
Drug Resistance, Neoplasm* / drug effects
Focal Adhesion Kinase 1* / antagonists & inhibitors
Focal Adhesion Kinase 1* / metabolism
Humans
Immunotherapy / methods
MAP Kinase Signaling System / drug effects
Melanoma* / drug therapy
Melanoma* / genetics
Melanoma* / immunology
Melanoma* / pathology
Mice
Mutation
Protein Kinase Inhibitors* / pharmacology
Proto-Oncogene Proteins B-raf* / antagonists & inhibitors
Proto-Oncogene Proteins B-raf* / genetics
Xenograft Model Antitumor Assays

Substances

Proto-Oncogene Proteins B-raf
BRAF protein, human
Protein Kinase Inhibitors
Focal Adhesion Kinase 1
PTK2 protein, human

Abstract

MeSH terms

Substances

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