Synapse - Multiomic analysis of lung tumors defines pathways activated in neuroendocrine transformation

Multiomic analysis of lung tumors defines pathways activated in neuroendocrine transformation Journal Article

Authors:	Quintanal-Villalonga, A.; Taniguchi, H.; Zhan, Y. A.; Hasan, M. M.; Chavan, S. S.; Meng, F.; Uddin, F.; Manoj, P.; Donoghue, M. T. A.; Won, H. H.; Chan, J. M.; Ciampricotti, M.; Chow, A.; Offin, M.; Chang, J. C.; Ray-Kirton, J.; Tischfield, S. E.; Egger, J.; Bhanot, U. K.; Linkov, I.; Asher, M.; Sinha, S.; Silber, J.; Iacobuzio-Donahue, C. A.; Roehrl, M. H.; Hollmann, T. J.; Yu, H. A.; Qiu, J.; de Stanchina, E.; Baine, M. K.; Rekhtman, N.; Poirier, J. T.; Loomis, B.; Koche, R. P.; Rudin, C. M.; Sen, T.
Article Title:	Multiomic analysis of lung tumors defines pathways activated in neuroendocrine transformation
Abstract:	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. Defi ning 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.
Keywords:	methylation; yap1; resistance; differentiation; prostate-cancer; heterogeneity; sclc; small-cell carcinoma
Journal Title:	Cancer Discovery
Volume:	11
Issue:	12
ISSN:	2159-8274
Publisher:	American Association for Cancer Research
Date Published:	2021-12-01
Start Page:	3028
End Page:	3047
Language:	English
ACCESSION:	WOS:000727272800001
DOI:	10.1158/2159-8290.Cd-20-1863
PROVIDER:	wos
PUBMED:	34155000
PMCID:	PMC9437746
Notes:	Article -- Source: Wos