Evidence map›Paper›PMID 40020669›Full record

ArticleCancer cell2025

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 and 10 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cancer cell, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.

0numbers the graph read from it
0cells of the map it votes in
33citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

33 citing papers in PubMed.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

20 authors.

Simone LubranoDepartment 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.
Rodolfo Daniel Cervantes-VillagranaMoores 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.
Farhoud FarajiMoores 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.
Sydney RamirezMoores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
Kuniaki SatoMoores 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.
Sendi R Adame-GarciaMoores 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.
Adam OfficerMoores 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.
Nadia ArangMoores 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.
Damiano C RigiraccioloMoores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
Paola Y Anguiano QuirozMoores 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.
Claudia MartiniDepartment of Pharmacy, University of Pisa, 56126 Pisa, Italy.
YiYu WangDepartment of Chemistry and Biochemistry and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA.
Fleur M FergusonDepartment of Chemistry and Biochemistry and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA.
Antonietta BacchiocchiDepartment of Dermatology, Yale University School of Medicine, New Haven, CT 06520, USA.
Ruth HalabanDepartment of Dermatology, Yale University School of Medicine, New Haven, CT 06520, USA.
Silvia ComaVerastem Oncology, Needham, MA 02494, USA.
Sheri L HolmenDepartment of Surgery, University of Utah Health Sciences Center, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
Jonathan A PachterVerastem Oncology, Needham, MA 02494, USA.
Andrew E AplinDepartment of Pharmacology, Physiology and Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, US.
J Silvio GutkindMoores 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.

Funding

TR&D 3 - Network Guided Machine LearningP41GM103504 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI IDEKER, TREY · 2012 to 2024
$17.3M
GRADUATE TRAINING IN CELLULAR &MOLECULAR PHARMACOLOGYT32GM007752 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI BROWN, JOAN HELLER, HANDEL, TRACY M · 1985 to 2023
$13.5M
Using Networks to Seed Hierarchical Whole-cell Models of CancerU54CA209891 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI IDEKER, TREY · 2017 to 2021
$10.9M
San Diego Biomedical Informatics Education & Research (SABER)T15LM011271 · NLM · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI SHAMIM NEMATI · 2012 to 2026
$9.7M
Efficacy of combined inhibition of BRAF, MEK, and FAK in melanoma patient derived xenograftsR01CA121118 · NCI · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · PI Sheri L Holmen · 2007 to 2026
$4.7M
Targeted therapies in mutant BRAF melanomaR01CA182635 · NCI · THOMAS JEFFERSON UNIVERSITY · PI APLIN, ANDREW ERIC · 2014 to 2024
$3.4M
Targeting Systems Vulnerabilities in the Gαq/GNAQ Oncogenic Signaling Circuitry: New Precision Therapies for Uveal MelanomaR01CA257505 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI APLIN, ANDREW ERIC, GUTKIND, JORGE SILVIO · 2021 to 2025
$2.7M
OTOLARYNGOLOGY TRAINING IN IMMUN., VIROL. &MOLEC. BIOL.T32DC000028 · NIDCD · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI RYAN, ALLEN F. · 1989 to 2020
$2.1M
NCI NIH HHS R01 CA121118NCI NIH HHS R01 CA182635NCI NIH HHS R01 CA257505NCI NIH HHS U54 CA209891NIDCD NIH HHS T32 DC000028NIGMS NIH HHS P41 GM103504NIGMS NIH HHS T32 GM007752NLM NIH HHS T15 LM011271
6 · The paper itself

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.

Indexed as

Antineoplastic Combined Chemotherapy ProtocolsDrug Resistance, NeoplasmFocal Adhesion Kinase 1MelanomaProtein Kinase InhibitorsProto-Oncogene Proteins B-rafAnimalsApoptosisCell Line, TumorHumansImmunotherapyMAP Kinase Signaling SystemMiceMutationXenograft Model Antitumor AssaysBRAF protein, humanFocal Adhesion Kinase 1Protein Kinase InhibitorsProto-Oncogene Proteins B-rafPTK2 protein, humanavutometinibBRAFFAKimmunotherapyMAPK signalingMEKmelanomaresistancesignal transductiontargeted therapies

Identifiers

PMID40020669
PMCPMC11903146

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.