Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities

被引：4

作者：

Chua, Khi Pin ^{[1
]}

Teng, Yvonne H. F. ^{[2
,3
]}

Tan, Aaron C. ^{[2
,4
]}

Takano, Angela ^{[5
]}

Alvarez, Jacob J. S. ^{[1
]}

Nahar, Rahul ^{[1
]}

Rohatgi, Neha ^{[1
]}

Lai, Gillianne G. Y. ^{[2
]}

Aung, Zaw Win ^{[2
]}

Yeong, Joe P. S. ^{[5
]}

Lim, Kiat Hon ^{[5
]}

Naeini, Marjan Mojtabavi ^{[1
]}

Kassam, Irfahan ^{[1
]}

Jain, Amit ^{[2
]}

Tan, Wan Ling ^{[2
]}

Gogna, Apoorva ^{[6
]}

Too, Chow Wei ^{[6
]}

Kanesvaran, Ravindran ^{[2
]}

Ng, Quan Sing ^{[2
]}

Ang, Mei Kim ^{[2
]}

Rajasekaran, Tanujaa ^{[2
]}

Anantham, Devanand ^{[7
]}

Phua, Ghee Chee ^{[7
]}

Tan, Bien Soo ^{[6
]}

Lee, Yin Yeng ^{[1
]}

Wang, Lanying ^{[2
]}

Teo, Audrey S. M. ^{[1
]}

Khng, Alexis Jiaying ^{[1
]}

Lim, Ming Jie ^{[1
]}

Suteja, Lisda ^{[2
]}

Toh, Chee Keong ^{[2
]}

Lim, Wan-Teck ^{[2
,4
,8
]}

Iyer, N. Gopalakrishna ^{[3
,4
,9
]}

Tam, Wai Leong ^{[1
,10
,11
,12
]}

Tan, Eng-Huat ^{[2
]}

Zhai, Weiwei ^{[1
,13
,14
]}

Hillmer, Axel M. ^{[1
,15
,16
]}

Skanderup, Anders J. ^{[1
]}

Tan, Daniel S. W. ^{[1
,2
,3
,4
]}

机构：

[1] Genome Inst Singapore, Singapore, Singapore

[2] Natl Canc Ctr Singapore, Div Med Oncol, Singapore, Singapore

[3] Natl Canc Ctr Singapore, Canc Therapeut Res Lab, Singapore, Singapore

[4] Duke NUS Med Sch Singapore, Singapore, Singapore

[5] Singapore Gen Hosp, Div Pathol, Singapore, Singapore

[6] Singapore Gen Hosp, Dept Vasc & Intervent Radiol, Singapore, Singapore

[7] Singapore Gen Hosp, Dept Resp & Crit Care Med, Singapore, Singapore

[8] Inst Mol & Cell Biol, IMCB NCC MPI Singapore Oncogenome Lab, Singapore, Singapore

[9] Natl Canc Ctr Singapore, Div Surg Oncol, Singapore, Singapore

[10] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore, Singapore

[11] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore, Singapore

[12] Nanyang Technol Univ, Sch Biol Sci, Singapore, Singapore

[13] Chinese Acad Sci, Inst Zool, Key Lab Zool Systemat & Evolut, Beijing, Peoples R China

[14] Chinese Acad Sci, Ctr Excellence Anim Evolut & Genet, Kunming, Yunnan, Peoples R China

[15] Univ Cologne, Fac Med, Inst Pathol, Cologne, Germany

[16] Univ Cologne, Univ Hosp Cologne, Cologne, Germany

来源：

CLINICAL CANCER RESEARCH | 2021年 / 27卷 / 21期

基金：

英国医学研究理事会; 新加坡国家研究基金会;

关键词：

CELL LUNG-CANCER; ACQUIRED-RESISTANCE; 1ST-LINE TREATMENT; OPEN-LABEL; CHECKPOINT INHIBITORS; GEFITINIB; OSIMERTINIB; EVOLUTION; AFATINIB;

D O I：

10.1158/1078-0432.CCR-20-4607

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：5939 / 5950

页数：12

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