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Targeting FGFR overcomes EMT-mediated resistance in EGFR mutant non-small cell lung cancer

Evolved resistance to tyrosine kinase inhibitor (TKI) targeted therapies remains a major clinical challenge. In EGFR mutant non-small cell lung cancer (NSCLC), failure of EGFR TKIs can result from both genetic and epigenetic mechanisms of acquired drug resistance. Widespread reports of histologic an...

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Autores principales: Raoof, Sana, Mulford, Iain J., Frisco-Cabanos, Heidie, Nangia, Varuna, Timonina, Daria, Labrot, Emma, Hafeez, Nafeeza, Bilton, Samantha J., Drier, Yotam, Ji, Fei, Greenberg, Max, Williams, August, Kattermann, Krystina, Damon, Leah, Sovath, Sosathya, Rakiec, Daniel P., Korn, Joshua M., Ruddy, David A., Benes, Cyril H., Hammerman, Peter S., Piotrowska, Zofia, Sequist, Lecia V., Niederst, Matthew J., Barretina, Jordi, Engelman, Jeffrey A., Hata, Aaron N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742540/
https://www.ncbi.nlm.nih.gov/pubmed/31324888
http://dx.doi.org/10.1038/s41388-019-0887-2
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author Raoof, Sana
Mulford, Iain J.
Frisco-Cabanos, Heidie
Nangia, Varuna
Timonina, Daria
Labrot, Emma
Hafeez, Nafeeza
Bilton, Samantha J.
Drier, Yotam
Ji, Fei
Greenberg, Max
Williams, August
Kattermann, Krystina
Damon, Leah
Sovath, Sosathya
Rakiec, Daniel P.
Korn, Joshua M.
Ruddy, David A.
Benes, Cyril H.
Hammerman, Peter S.
Piotrowska, Zofia
Sequist, Lecia V.
Niederst, Matthew J.
Barretina, Jordi
Engelman, Jeffrey A.
Hata, Aaron N.
author_facet Raoof, Sana
Mulford, Iain J.
Frisco-Cabanos, Heidie
Nangia, Varuna
Timonina, Daria
Labrot, Emma
Hafeez, Nafeeza
Bilton, Samantha J.
Drier, Yotam
Ji, Fei
Greenberg, Max
Williams, August
Kattermann, Krystina
Damon, Leah
Sovath, Sosathya
Rakiec, Daniel P.
Korn, Joshua M.
Ruddy, David A.
Benes, Cyril H.
Hammerman, Peter S.
Piotrowska, Zofia
Sequist, Lecia V.
Niederst, Matthew J.
Barretina, Jordi
Engelman, Jeffrey A.
Hata, Aaron N.
author_sort Raoof, Sana
collection PubMed
description Evolved resistance to tyrosine kinase inhibitor (TKI) targeted therapies remains a major clinical challenge. In EGFR mutant non-small cell lung cancer (NSCLC), failure of EGFR TKIs can result from both genetic and epigenetic mechanisms of acquired drug resistance. Widespread reports of histologic and gene expression changes consistent with an epithelial-to-mesenchymal transition (EMT) have been associated with initially surviving drug tolerant persister cells, which can seed bona fide genetic mechanisms of resistance to EGFR TKIs. While therapeutic approaches targeting fully resistant cells, such as those harboring an EGFR(T790M) mutation, have been developed, a clinical strategy for preventing the emergence of persister cells remains elusive. Using mesenchymal cell lines derived from biopsies of patients who progressed on EGFR TKI as surrogates for persister populations, we performed whole-genome CRISPR screening and identified FGFR1 as the top target promoting survival of mesenchymal EGFR mutant cancers. Although numerous previous reports of FGFR signaling contributing to EGFR TKI resistance in vitro exist, the data has not yet been sufficiently compelling to instigate a clinical trial testing this hypothesis, nor has the role of FGFR in promoting the survival of persister cells been elucidated. In this study, we find that combining EGFR and FGFR inhibitors inhibited the survival and expansion of EGFR mutant drug tolerant cells over long time periods, preventing the development of fully resistant cancers in multiple vitro models and in vivo. These results suggest that dual EGFR and FGFR blockade may be a promising clinical strategy for both preventing and overcoming EMT-associated acquired drug resistance and provide motivation for clinical study of combined EGFR and FGFR inhibition in EGFR-mutated NSCLCs.
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spelling pubmed-67425402020-01-19 Targeting FGFR overcomes EMT-mediated resistance in EGFR mutant non-small cell lung cancer Raoof, Sana Mulford, Iain J. Frisco-Cabanos, Heidie Nangia, Varuna Timonina, Daria Labrot, Emma Hafeez, Nafeeza Bilton, Samantha J. Drier, Yotam Ji, Fei Greenberg, Max Williams, August Kattermann, Krystina Damon, Leah Sovath, Sosathya Rakiec, Daniel P. Korn, Joshua M. Ruddy, David A. Benes, Cyril H. Hammerman, Peter S. Piotrowska, Zofia Sequist, Lecia V. Niederst, Matthew J. Barretina, Jordi Engelman, Jeffrey A. Hata, Aaron N. Oncogene Article Evolved resistance to tyrosine kinase inhibitor (TKI) targeted therapies remains a major clinical challenge. In EGFR mutant non-small cell lung cancer (NSCLC), failure of EGFR TKIs can result from both genetic and epigenetic mechanisms of acquired drug resistance. Widespread reports of histologic and gene expression changes consistent with an epithelial-to-mesenchymal transition (EMT) have been associated with initially surviving drug tolerant persister cells, which can seed bona fide genetic mechanisms of resistance to EGFR TKIs. While therapeutic approaches targeting fully resistant cells, such as those harboring an EGFR(T790M) mutation, have been developed, a clinical strategy for preventing the emergence of persister cells remains elusive. Using mesenchymal cell lines derived from biopsies of patients who progressed on EGFR TKI as surrogates for persister populations, we performed whole-genome CRISPR screening and identified FGFR1 as the top target promoting survival of mesenchymal EGFR mutant cancers. Although numerous previous reports of FGFR signaling contributing to EGFR TKI resistance in vitro exist, the data has not yet been sufficiently compelling to instigate a clinical trial testing this hypothesis, nor has the role of FGFR in promoting the survival of persister cells been elucidated. In this study, we find that combining EGFR and FGFR inhibitors inhibited the survival and expansion of EGFR mutant drug tolerant cells over long time periods, preventing the development of fully resistant cancers in multiple vitro models and in vivo. These results suggest that dual EGFR and FGFR blockade may be a promising clinical strategy for both preventing and overcoming EMT-associated acquired drug resistance and provide motivation for clinical study of combined EGFR and FGFR inhibition in EGFR-mutated NSCLCs. 2019-07-19 2019-09 /pmc/articles/PMC6742540/ /pubmed/31324888 http://dx.doi.org/10.1038/s41388-019-0887-2 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Raoof, Sana
Mulford, Iain J.
Frisco-Cabanos, Heidie
Nangia, Varuna
Timonina, Daria
Labrot, Emma
Hafeez, Nafeeza
Bilton, Samantha J.
Drier, Yotam
Ji, Fei
Greenberg, Max
Williams, August
Kattermann, Krystina
Damon, Leah
Sovath, Sosathya
Rakiec, Daniel P.
Korn, Joshua M.
Ruddy, David A.
Benes, Cyril H.
Hammerman, Peter S.
Piotrowska, Zofia
Sequist, Lecia V.
Niederst, Matthew J.
Barretina, Jordi
Engelman, Jeffrey A.
Hata, Aaron N.
Targeting FGFR overcomes EMT-mediated resistance in EGFR mutant non-small cell lung cancer
title Targeting FGFR overcomes EMT-mediated resistance in EGFR mutant non-small cell lung cancer
title_full Targeting FGFR overcomes EMT-mediated resistance in EGFR mutant non-small cell lung cancer
title_fullStr Targeting FGFR overcomes EMT-mediated resistance in EGFR mutant non-small cell lung cancer
title_full_unstemmed Targeting FGFR overcomes EMT-mediated resistance in EGFR mutant non-small cell lung cancer
title_short Targeting FGFR overcomes EMT-mediated resistance in EGFR mutant non-small cell lung cancer
title_sort targeting fgfr overcomes emt-mediated resistance in egfr mutant non-small cell lung cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742540/
https://www.ncbi.nlm.nih.gov/pubmed/31324888
http://dx.doi.org/10.1038/s41388-019-0887-2
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