{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:54:09Z","timestamp":1785430449452,"version":"3.56.0"},"posted":{"date-parts":[[2025,5,9]]},"group-title":"Cancer Biology","reference-count":55,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T00:00:00Z","timestamp":1746748800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"award":["F32CA228267"],"award-info":[{"award-number":["F32CA228267"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["K99CA246084"],"award-info":[{"award-number":["K99CA246084"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R00CA246084"],"award-info":[{"award-number":["R00CA246084"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["CA131261-09S2"],"award-info":[{"award-number":["CA131261-09S2"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004917","name":"Cancer Prevention and Research Institute of Texas","doi-asserted-by":"crossref","award":["R220062"],"award-info":[{"award-number":["R220062"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  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, BRAF\n                  <jats:sup>V600E<\/jats:sup>\n                  signaling promotes expression of ligands including\n                  <jats:italic>HB-EGF<\/jats:italic>\n                  ,\n                  <jats:italic>TGF\u03b1<\/jats:italic>\n                  ,\n                  <jats:italic>Epi-<\/jats:italic>\n                  and\n                  <jats:italic>Amphiregulin<\/jats:italic>\n                  . 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 BRAF\n                  <jats:sup>V600E<\/jats:sup>\n                  -driven lung tumorigenesis and supports late-stage BRAF\n                  <jats:sup>V600E<\/jats:sup>\n                  -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\n                  <jats:italic>BRAF<\/jats:italic>\n                  -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 BRAF\n                  <jats:sup>V600E<\/jats:sup>\n                  -driven lung cancer by combined inhibition of both BRAF\n                  <jats:sup>V600E<\/jats:sup>\n                  signaling plus pan-ERBB signaling. Collectively, this work provides evidence for an important role for ERBB family signaling in the genesis and maintenance of BRAF\n                  <jats:sup>V600E<\/jats:sup>\n                  -driven lung cancers, and the potential for future therapeutic improvement by rational combination targeting of these pathways.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>SIGNIFICANCE<\/jats:title>\n                  <jats:p>\n                    <jats:italic>\n                      BRAF\n                      <jats:sup>T1799A<\/jats:sup>\n                    <\/jats:italic>\n                    serves as a predictive biomarker for FDA-approved targeted inhibition of BRAF\n                    <jats:sup>V600E<\/jats:sup>\n                    oncoprotein kinase signaling in non-small cell lung cancer (NSCLC). However the occurrence of primary or acquired drug resistance limit the depth and durability of patient responses. Studies described here provide a mechanistic rationale for clinical testing of first-line BRAF\n                    <jats:sup>V600E<\/jats:sup>\n                    inhibition combined with pan-ERBB inhibition to improve the depth and durability of initial patient responses, and delay the emergence of lethal drug resistant disease.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.05.04.652129","type":"posted-content","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T07:30:16Z","timestamp":1746775816000},"source":"Crossref","is-referenced-by-count":0,"title":["BRAF\n                  <sup>V600E<\/sup>\n                  -Driven Lung Tumorigenesis Requires Ligand-Mediated Activation of ERBB Receptor Signaling"],"prefix":"10.64898","author":[{"given":"Melanie Angelina","family":"Dacheux","sequence":"first","affiliation":[{"name":"Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, 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Sloan Kettering, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Gumbleton","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Utah, Salt Lake City, Utah"},{"name":"The Division of Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonam","family":"Puri","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Utah, Salt Lake City, Utah"},{"name":"The Division of Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wallace","family":"Akerley","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Utah, Salt Lake City, Utah"},{"name":"The Division of Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt 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