Multiomic Analysis of Lung Tumors Defines Pathways Activated in Neuroendocrine Transformation | Zendy

Álvaro Quintanal-Villalonga | Zendy; Hirokazu Taniguchi | Zendy; Yingqian A. Zhan | Zendy; Maysun Hasan | Zendy; Shweta S. Chavan | Zendy; Fanli Meng | Zendy; Fathema Uddin | Zendy; Parvathy Manoj | Zendy; Mark T.A. Donoghue | Zendy; Helen Won | Zendy; Joseph M. Chan | Zendy; Metamia Ciampricotti | Zendy; Andrew Chow | Zendy; Michael Offin | Zendy; Jason C. Chang | Zendy; Jordana Ray-Kirton | Zendy; Sam E. Tischfield | Zendy; Jacklynn V. Egger | Zendy; Umesh Bhanot | Zendy; Irina Linkov | Zendy; Marina Asher | Zendy; S. K. Sinha | Zendy; Joachim Silber | Zendy; Christine A. IacobuzioDonahue | Zendy; Michael H. A. Roehrl | Zendy; Travis J. Hollmann | Zendy; Helena A. Yu | Zendy; Juan Qiu | Zendy; Elisa de Stanchina | Zendy; Marina K. Baine | Zendy; Natasha Rekhtman | Zendy; John T. Poirier | Zendy; Brian HouckLoomis | Zendy; Richard P. Koche | Zendy; Charles M. Rudin | Zendy; Triparna Sen | Zendy

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Multiomic Analysis of Lung Tumors Defines Pathways Activated in Neuroendocrine Transformation

Author(s) -

Álvaro Quintanal-Villalonga,

Hirokazu Taniguchi,

Yingqian A. Zhan,

Maysun Hasan,

Shweta S. Chavan,

Fanli Meng,

Fathema Uddin,

Parvathy Manoj,

Mark T.A. Donoghue,

Helen Won,

Joseph M. Chan,

Metamia Ciampricotti,

Andrew Chow,

Michael Offin,

Jason C. Chang,

Jordana Ray-Kirton,

Sam E. Tischfield,

Jacklynn V. Egger,

Umesh Bhanot,

Irina Linkov,

Marina Asher,

S. K. Sinha,

Joachim Silber,

Christine A. IacobuzioDonahue,

Michael H. A. Roehrl,

Travis J. Hollmann,

Helena A. Yu,

Juan Qiu,

Elisa de Stanchina,

Marina K. Baine,

Natasha Rekhtman,

John T. Poirier,

Brian HouckLoomis,

Richard P. Koche,

Charles M. Rudin,

Triparna Sen

Publication year - 2021

Publication title -

cancer discovery

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.795

H-Index - 163

eISSN - 2159-8290

pISSN - 2159-8274

DOI - 10.1158/2159-8290.cd-20-1863

Subject(s) - transformation (genetics) , neuroendocrine tumors , lung , cancer research , computational biology , biology , microbiology and biotechnology , computer science , pathology , medicine , genetics , gene

Lineage plasticity is implicated in treatment resistance in multiple cancers. In lung adenocarcinomas (LUAD) amenable to targeted therapy, transformation to small cell lung cancer (SCLC) is a recognized resistance mechanism. Defining molecular mechanisms of neuroendocrine (NE) transformation in lung cancer has been limited by a paucity of pre/posttransformation clinical samples. Detailed genomic, epigenomic, transcriptomic, and protein characterization of combined LUAD/SCLC tumors, as well as pre/posttransformation samples, supports that NE transformation is primarily driven by transcriptional reprogramming rather than mutational events. We identify genomic contexts in which NE transformation is favored, including frequent loss of the 3p chromosome arm. We observed enhanced expression of genes involved in the PRC2 complex and PI3K/AKT and NOTCH pathways. Pharmacologic inhibition of the PI3K/AKT pathway delayed tumor growth and NE transformation in an EGFR-mutant patient-derived xenograft model. Our findings define a novel landscape of potential drivers and therapeutic vulnerabilities of NE transformation in lung cancer.

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