{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:19:32Z","timestamp":1792790372470,"version":"4.5.0"},"posted":{"date-parts":[[2026,10,2]]},"group-title":"Cancer Biology","reference-count":58,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["K01OD031811"],"award-info":[{"award-number":["K01OD031811"]}]},{"name":"National Cancer Institute","award":["1R01CA300732"],"award-info":[{"award-number":["1R01CA300732"]}]},{"name":"Sam Day Foundation"},{"name":"MIB Agents\/ Fishin\u2019 For The Cure","id":[{"id":"https:\/\/ror.org\/053pqtj30","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Purpose<\/jats:title>\n                  <jats:p>Lung metastases are the primary cause of death in osteosarcoma patients and treatment response often vary due to convergence of genetic and phenotypic influences in the context of a dynamic tumor-host tissue environment. The purpose of this study was to determine how dynamic tumor- and host-driven receptor tyrosine kinase (RTK)-ERK signaling interactions contribute to phenotypic drug response heterogeneity.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Experimental Design<\/jats:title>\n                  <jats:p>\n                    Live-cell time-lapse microscopy and data-driven dynamical modeling was used to resolve ERK activity, FOSL1\/Fra-1 reporter expression, and spatiotemporal cell fate in living, biosensor-expressing osteosarcoma lung metastases\n                    <jats:italic>ex vivo<\/jats:italic>\n                    following MCL1 inhibitor exposure. RTK inhibitors were then evaluated for their ability to suppress adaptive signaling and enhance MCL1 inhibitor efficacy\n                    <jats:italic>ex vivo<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    .\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    MCL1 inhibition induced extensive tumor-cell death; however, persistent ERK\n                    <jats:sub>high<\/jats:sub>\n                    \/Fra-1\n                    <jats:sub>high<\/jats:sub>\n                    reporter cells emerged and were enriched at the tumor-lung interface, consistent with adaptive resistance. Experimental and computational approaches revealed that tumor-cell lysis amplified fibroblast growth factor receptor (FGFR)-mediated ERK signaling in neighboring cells, promoting a targetable drug-resistant state marked by adaptive ERK induction, FOSL1\/Fra-1 expression, and correlated with upregulation of known drug resistance pathways Nrf2 and HMOX1. Combinatorial inhibition of FGFR with fexagratinib, or broad-spectrum RTK inhibitor, pazopanib, suppressed adaptive ERK activation and enhanced MCL1 inhibitor response resulting in greater efficacy\n                    <jats:italic>ex vivo<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    .\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Tumor-host and tumor-cell-lysis-induced FGFR-ERK signaling contribute to spatiotemporally heterogeneous adaptive resistance in metastatic osteosarcoma. These data support combinatorial targeting of RTK signaling with cytotoxic or targeted agents as a strategy to block adaptive resistance and improve treatment efficacy.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.30.755770","type":"posted-content","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T08:20:12Z","timestamp":1790929212000},"source":"Crossref","is-referenced-by-count":0,"title":["Spatially coordinated RTK-ERK signaling dynamics shape osteosarcoma single-cell drug response in the lung microenvironment"],"prefix":"10.64898","author":[{"given":"Rawan","family":"Makkawi","sequence":"first","affiliation":[{"name":"Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Halsey","sequence":"additional","affiliation":[{"name":"Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vaibhav","family":"Murthy","sequence":"additional","affiliation":[{"name":"Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elise C.","family":"Manalo","sequence":"additional","affiliation":[{"name":"Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugo","family":"Cros","sequence":"additional","affiliation":[{"name":"Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Yi","sequence":"additional","affiliation":[{"name":"Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessie May","family":"Cartier","sequence":"additional","affiliation":[{"name":"Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Chang","sequence":"additional","affiliation":[{"name":"Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Flory","sequence":"additional","affiliation":[{"name":"Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Guptell","sequence":"additional","affiliation":[{"name":"Center for Childhood Cancers and Blood Diseases, Abigail Wexner Research Institute at Nationwide Children\u2019s Hospital, Columbus, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Gross","sequence":"additional","affiliation":[{"name":"Center for Childhood Cancers and Blood Diseases, Abigail Wexner Research Institute at Nationwide Children\u2019s Hospital, Columbus, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan D.","family":"Roberts","sequence":"additional","affiliation":[{"name":"Center for Childhood Cancers and Blood Diseases, Abigail Wexner Research Institute at Nationwide Children\u2019s Hospital, Columbus, OH, USA"},{"name":"Division of Pediatric Hematology, Oncology, and BMT, Nationwide Children\u2019s Hospital, Columbus, OH, USA"},{"name":"The Ohio State University James Comprehensive Cancer Center, Columbus, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Copperman","sequence":"additional","affiliation":[{"name":"Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1917-8816","authenticated-orcid":false,"given":"Alexander E.","family":"Davies","sequence":"additional","affiliation":[{"name":"Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA"},{"name":"Division of Oncological Sciences, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA"},{"name":"Department of Pediatrics, School of Medicine, Oregon Health and Science University, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026100609152467000_2026.09.30.755770v1.1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.32351"},{"key":"2026100609152467000_2026.09.30.755770v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2018.11.027"},{"key":"2026100609152467000_2026.09.30.755770v1.3","doi-asserted-by":"crossref","unstructured":"Y Y, Z H, M Y, J R, R C, T J, et al. 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