2. Academic Validation
  3. BRAFV600E-Driven Lung Tumorigenesis Requires Ligand-Mediated Activation of ERBB Receptor Signaling

BRAFV600E-Driven Lung Tumorigenesis Requires Ligand-Mediated Activation of ERBB Receptor Signaling

  • bioRxiv. 2025 May 9:2025.05.04.652129. doi: 10.1101/2025.05.04.652129.
Melanie Angelina Dacheux 1,  Meng-Jung Wu 1,  Michael T Scherzer 2,  Monique Nillson 3,  Brandon Murphy 2,  Sophia Schuman 2,  Zhenlin Ju 4,  Trever Bivona 5,  Piro Lito 6,  Matthew Gumbleton 7 8,  Sonam Puri 7 8,  Wallace Akerley 7 8,  Jing Wang 4,  Kaiwen Wang 9,  John Heymach 3,  Conan G Kinsey 2 7 8,  Marcelo Negrao 3,  Martin McMahon 2 10,  Aria Vaishnavi 1 3
Affiliations

Affiliations

  • 1 Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 2 Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
  • 3 Department of Thoracic Head & Neck Medical Oncology University of Texas Cancer Center, Houston, Texas.
  • 4 Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 5 Department of Medicine, Division of Hematology and Oncology, University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, California.
  • 6 Human Oncology and Pathogenesis Program and the Department of Medicine, Memorial Sloan Kettering, New York, New York.
  • 7 Department of Internal Medicine, University of Utah, Salt Lake City, Utah.
  • 8 The Division of Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT.
  • 9 Division of Pharmacy, University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 10 Department of Dermatology, University of Utah, Salt Lake City, UT.
PMID: 40654950 DOI: 10.1101/2025.05.04.652129
Abstract

Secretion of ligands of the human epidermal growth factor (EGFR) family of receptors or erythroblastic leukemia viral oncogene family (ERBB1-4) is a feature common to many Cancer cells. However, our understanding of the role of autocrine ligands in the aberrant behavior of Cancer remains incomplete. Here we demonstrate that, in numerous preclinical models of lung tumorigenesis, BRAFV600E signaling promotes expression of ligands including HB-EGF, TGFα, Epi- and Amphiregulin. Moreover, using both genetic or pharmacological approaches, we demonstrate that ligand-mediated activation of EGFR signaling in the tumor cell is required to sustain both early-stage BRAFV600E-driven lung tumorigenesis and supports late-stage BRAFV600E-driven lung Cancer maintenance. Unbiased Reverse Phase Protein Analyses (RPPA) analyses, paired with targeted validation, reveals ERBB signaling serves to sustain signaling through the ERK1/2 MAP kinase pathway, through effects on ARAF and CRAF, and on the parallel JUN kinase (JNK) pathway. Furthermore, EGFR is activated in a cohort of BRAF-mutated lung Cancer patients both pre- and post-treatment. Finally, we noted significant improvement in the depth and durability of therapeutic responses in preclinical models of BRAFV600E-driven lung Cancer by combined inhibition of both BRAFV600E signaling plus pan-ERBB signaling. Collectively, this work provides evidence for an important role for ERBB family signaling in the genesis and maintenance of BRAFV600E-driven lung cancers, and the potential for future therapeutic improvement by rational combination targeting of these pathways.

Keywords

BRAFV600E oncoprotein kinase; ERBB/EGFR signaling; Genetically engineered mouse models of lung cancer; Pathway-targeted therapy.

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