Evidence map›Paper›PMID 41654519›Full record

ArticleNature communications2026

Pan-RAF inhibitor exarafenib targets BRAF class II/III NSCLC and reveals ARAF-KSR1 resistance and combination strategies.

Tadashi Manabe, Hannah C Bergo, Qingtian Li, Tim Sen Wang, Paul Severson, Nichol Miller, Catherine Lee, Elifnur Yay Donderici, Nicole Zhang, Wei Wu and 14 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing 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

5 citing papers in PubMed.

  1. Review
  2. Review
  3. Review
  4. Review
  5. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

24 authors.

Tadashi ManabeDepartment of Medicine, University of California, San Francisco, San Francisco, CA, USA. tadashi.manabe@ucsf.edu.ORCID 0000-0001-9891-5222
Hannah C BergoDepartment of Medicine, University of California, San Francisco, San Francisco, CA, USA.ORCID 0009-0007-1879-0791
Qingtian LiDepartment of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Tim Sen WangKinnate Biopharma, San Diego, CA, USA.
Paul SeversonKinnate Biopharma, San Diego, CA, USA.ORCID 0009-0008-6762-6557
Nichol MillerKinnate Biopharma, San Diego, CA, USA.
Catherine LeeKinnate Biopharma, San Diego, CA, USA.ORCID 0000-0002-3105-3557
Elifnur Yay DondericiGuardant Health, Redwood City, CA, USA.
Nicole ZhangGuardant Health, Redwood City, CA, USA.ORCID 0009-0001-2706-5838
Wei WuDepartment of Medicine, University of California, San Francisco, San Francisco, CA, USA.ORCID 0000-0002-6556-067X
Yu-Ting ChouDepartment of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Daniel L KerrDepartment of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Paul AllegakoenDepartment of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Kathryn B GrandinettiKinnate Biopharma, San Diego, CA, USA.ORCID 0009-0000-6917-0372
Liliana SoroceanuKinnate Biopharma, San Diego, CA, USA.
Robert J PelhamKinnate Biopharma, San Diego, CA, USA.
Eric S MartinKinnate Biopharma, San Diego, CA, USA.
Eric A MurphyKinnate Biopharma, San Diego, CA, USA.
Vishesh KhannaDivision of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Joel W NealDivision of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.ORCID 0000-0003-3119-9334
Christopher T ChenDivision of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Shumei KatoDivision of Hematology and Oncology, University of California San Diego, Moores Cancer Center, La Jolla, CA, USA.ORCID 0000-0003-1193-1815
Richard WilliamsKinnate Biopharma, San Diego, CA, USA.
Trever G BivonaDepartment of Medicine, University of California, San Francisco, San Francisco, CA, USA. trever.bivona@ucsf.edu.ORCID 0000-0001-5734-4128

Funding

UCSF Project 1U54CA224081 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Trever G Bivona · 2017 to 2026
$12.9M
The Cancer Target Discovery and Development Network at UCSFU01CA217882 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI BANDYOPADHYAY, SOURAV, BIVONA, TREVER G · 2017 to 2021
$5.2M
Characterization of YAP as a rational companion target in lung cancerR01CA204302 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Trever G Bivona · 2017 to 2026
$3.7M
Optimizing biologically-based rational polytherapy in ALK+ lung cancerR01CA211052 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI BIVONA, TREVER G · 2017 to 2021
$1.8M
U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R01CA204302U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R01CA211052U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) U01CA217882U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) U54CA224081
6 · The paper itself

Abstract

Oncogenic BRAF mutations, including those in non-small cell lung cancer (NSCLC), are classified as Class I, II, or III. While approved therapies exist for BRAF Class I mutants, no approved therapies exist for Class II and III BRAF-mutated NSCLC. Analysis of a circulating tumor DNA database reveals Class II and III mutations comprise ~65% of BRAF-mutant NSCLC cases, with Class II patients showing worse outcomes than Class I. Exarafenib, a distinct pan-RAF inhibitor, demonstrates potent activity against BRAF Class II and III mutant preclinical models and initial clinical activity. Resistance studies reveal rewiring to an ARAF-mediated bypass pathway, characterized by RAS-mediated ARAF-KSR1 complexes maintaining MAPK signaling despite pan-RAF inhibitor treatment. RAS or MEK inhibition co-targeting is effective against this resistance mechanism. This study provides preclinical rationale for clinical testing of exarafenib in BRAF Class II/III cancers and unveils RAS-mediated ARAF-KSR1 complex formation as a resistance mechanism and rational co-therapy strategies.

Indexed as

Carcinoma, Non-Small-Cell LungDrug Resistance, NeoplasmLung NeoplasmsProtein Kinase InhibitorsProtein KinasesProto-Oncogene Proteins B-rafAnimalsCell Line, TumorHumansMiceMutationXenograft Model Antitumor AssaysBRAF protein, humanKSR-1 protein kinaseProtein Kinase InhibitorsProtein KinasesProto-Oncogene Proteins B-raf

Identifiers

PMID41654519
PMCPMC12992618

What OpenQuestion holds

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Registered trials

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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.