1. Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities
- Author
-
Chua, Khi Pin, Teng, Yvonne H. F., Tan, Aaron C., Takano, Angela, 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, 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, Iyer, N. Gopalakrishna, Tam, Wai Leong, Tan, Eng-Huat, Zhai, Weiwei, Hillmer, Axel M., Skanderup, Anders J., Tan, Daniel S. W., Chua, Khi Pin, Teng, Yvonne H. F., Tan, Aaron C., Takano, Angela, 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, 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, Iyer, N. Gopalakrishna, Tam, Wai Leong, Tan, Eng-Huat, Zhai, Weiwei, Hillmer, Axel M., Skanderup, Anders J., and Tan, Daniel S. W.
- 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.
- Published
- 2021