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

We performed whole exome and transcriptome analysis of 59 first- and second-generation EGFR TKI resistant metastatic EGFR mutated patients to characterize and compare molecular alterations mediating resistance in T790M positive and negative disease. Transcriptomic analysis revealed ubiquitous loss of adenocarcinoma lineage gene expression in T790M negative tumors, orthogonally validated using multiplex immunohistochemistry. There was enrichment of genomic features such as TP53 alterations, 3q chromosomal amplifications, whole genome doubling and non-aging mutational signatures in T790M negative tumors. Almost half of resistant tumors were further classified as Immunehot, with clinical outcomes conditional on immune cell infiltration state and T790M status. Finally, using a Bayesian statistical approach, we explored how T790M negative and positive disease might be predicted using comprehensive genomic and transcriptomic profiles of treatment-naïve patients.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

1 Dataset 2 Publications

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD00001010272	Contains WES and RNA-seq for the 59 patients with first- and second-generation EGFR TKI-resistant metastatic EGFR-mutated NSCLC.		179

Publications	Citations
Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities. Chua KP, Teng YHF, Tan AC, Takano A, Alvarez JJS, Nahar R, Rohatgi N, Lai GGY, Aung ZW, Yeong JPS, Lim KH, Naeini MM, Kassam I, Jain A, Tan WL, Gogna A, Too CW, Kanesvaran R, Ng QS, Ang MK, Rajasekaran T, Anantham D, Phua GC, Tan BS, Lee YY, Wang L, Teo ASM, Khng AJ, Lim MJ, Suteja L, Toh CK, Lim WT, Iyer NG, Tam WL, Tan EH, Zhai W, Hillmer AM, Skanderup AJ, Tan DSW. Clin Cancer Res 27: 2021 5939-5950	13
CD70 is a therapeutic target upregulated in EMT-associated EGFR tyrosine kinase inhibitor resistance. Nilsson MB, Yang Y, Heeke S, Patel SA, Poteete A, Udagawa H, Elamin YY, Moran CA, Kashima Y, Arumugam T, Yu X, Ren X, Diao L, Shen L, Wang Q, Zhang M, Robichaux JP, Shi C, Pfeil AN, Tran H, Gibbons DL, Bock J, Wang J, Minna JD, Kobayashi SS, Le X, Heymach JV. Cancer Cell 41: 2023 340-355.e6	25

Publications

Citations

Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities.
Chua KP, Teng YHF, Tan AC, Takano A, Alvarez JJS, Nahar R, Rohatgi N, Lai GGY, Aung ZW, Yeong JPS, Lim KH, Naeini MM, Kassam I, Jain A, Tan WL, Gogna A, Too CW, Kanesvaran R, Ng QS, Ang MK, Rajasekaran T, Anantham D, Phua GC, Tan BS, Lee YY, Wang L, Teo ASM, Khng AJ, Lim MJ, Suteja L, Toh CK, Lim WT, Iyer NG, Tam WL, Tan EH, Zhai W, Hillmer AM, Skanderup AJ, Tan DSW. Clin Cancer Res 27: 2021 5939-5950

CD70 is a therapeutic target upregulated in EMT-associated EGFR tyrosine kinase inhibitor resistance.
Nilsson MB, Yang Y, Heeke S, Patel SA, Poteete A, Udagawa H, Elamin YY, Moran CA, Kashima Y, Arumugam T, Yu X, Ren X, Diao L, Shen L, Wang Q, Zhang M, Robichaux JP, Shi C, Pfeil AN, Tran H, Gibbons DL, Bock J, Wang J, Minna JD, Kobayashi SS, Le X, Heymach JV. Cancer Cell 41: 2023 340-355.e6