Chua, Khi Pin ORCID: 0000-0002-0083-0181, Teng, Yvonne H. F., Tan, Aaron C., Takano, Angela ORCID: 0000-0002-7830-8430, Alvarez, Jacob J. S., Nahar, Rahul, Rohatgi, Neha, Lai, Gillianne G. Y., Aung, Zaw Win, Yeong, Joe P. S., Lim, Kiat Hon, Naeini, Marjan Mojtabavi, Kassam, Irfahan ORCID: 0000-0002-6150-5614, Jain, Amit, Tan, Wan Ling, Gogna, Apoorva, Too, Chow Wei, Kanesvaran, Ravindran, Ng, Quan Sing, Ang, Mei Kim, Rajasekaran, Tanujaa, Anantham, Devanand, Phua, Ghee Chee, Tan, Bien Soo, Lee, Yin Yeng, Wang, Lanying, Teo, Audrey S. M., Khng, Alexis Jiaying, Lim, Ming Jie, Suteja, Lisda, Toh, Chee Keong, Lim, Wan-Teck ORCID: 0000-0002-4655-0206, Iyer, N. Gopalakrishna, Tam, Wai Leong ORCID: 0000-0003-2365-5264, Tan, Eng-Huat, Zhai, Weiwei, Hillmer, Axel M., Skanderup, Anders J. and Tan, Daniel S. W. (2021). Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities. Clin. Cancer Res., 27 (21). S. 5939 - 5951. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1557-3265

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Abstract

Purpose: Despite the established role of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutated NSCLC, drug resistance inevitably ensues, with a paucity of treatment options especially in EGFRT790M-negative resistance. Experimental Design: We performed whole-exome and transcriptome analysis of 59 patients with first- and second-generation EGFR TKI-resistant metastatic EGFR-mutated NSCLC to characterize and compare molecular alterations mediating resistance in T790M-positive (T790M(+)) and -negative (T790M(-)) disease. Results: Transcriptomic analysis revealed ubiquitous loss of adenocarcinoma lineage gene expression in T790M(-) tumors, orthogonally validated using multiplex IHC. There was enrichment of genomic features such as TP53 alterations, 3q chromosomal amplifications, whole-genome doubling and nonaging mutational signatures in T790M(-) tumors. Almost half of resistant tumors were further classified as immune(hot), with clinical outcomes conditional on immune cell-infiltration state and T790M status. Finally, using a Bayesian statistical approach, we explored how T790M(-) and T790M(+) disease might be predicted using comprehensive genomic and transcriptomic profiles of treatment-naive patients. Conclusions: Our results illustrate the interplay between genetic alterations, cell lineage plasticity, and immune microenvironment in shaping divergent TKI resistance and outcome trajectories in EGFR-mutated NSCLC. Genomic and transcriptomic profiling may facilitate the design of bespoke therapeutic approaches tailored to a tumor's adaptive potential.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Chua, Khi PinUNSPECIFIEDorcid.org/0000-0002-0083-0181UNSPECIFIED
Teng, Yvonne H. F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tan, Aaron C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Takano, AngelaUNSPECIFIEDorcid.org/0000-0002-7830-8430UNSPECIFIED
Alvarez, Jacob J. S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nahar, RahulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rohatgi, NehaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lai, Gillianne G. Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aung, Zaw WinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yeong, Joe P. S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lim, Kiat HonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Naeini, Marjan MojtabaviUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kassam, IrfahanUNSPECIFIEDorcid.org/0000-0002-6150-5614UNSPECIFIED
Jain, AmitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tan, Wan LingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gogna, ApoorvaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Too, Chow WeiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kanesvaran, RavindranUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ng, Quan SingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ang, Mei KimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rajasekaran, TanujaaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Anantham, DevanandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Phua, Ghee CheeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tan, Bien SooUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lee, Yin YengUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, LanyingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Teo, Audrey S. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khng, Alexis JiayingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lim, Ming JieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Suteja, LisdaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toh, Chee KeongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lim, Wan-TeckUNSPECIFIEDorcid.org/0000-0002-4655-0206UNSPECIFIED
Iyer, N. GopalakrishnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tam, Wai LeongUNSPECIFIEDorcid.org/0000-0003-2365-5264UNSPECIFIED
Tan, Eng-HuatUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhai, WeiweiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hillmer, Axel M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Skanderup, Anders J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tan, Daniel S. W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-600086
DOI: 10.1158/1078-0432.CCR-20-4607
Journal or Publication Title: Clin. Cancer Res.
Volume: 27
Number: 21
Page Range: S. 5939 - 5951
Date: 2021
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 1557-3265
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CELL LUNG-CANCER; ACQUIRED-RESISTANCE; 1ST-LINE TREATMENT; OPEN-LABEL; CHECKPOINT INHIBITORS; GEFITINIB; OSIMERTINIB; EVOLUTION; AFATINIBMultiple languages
OncologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60008

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