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Review
. 2020 May;12(5):2883-2895.
doi: 10.21037/jtd.2020.03.78.

Impact of concurrent genomic alterations in epidermal growth factor receptor (EGFR)-mutated lung cancer

Beatrice Gini  1   2 , Nicholas Thomas  1   2 , Collin M Blakely  1   2
Affiliations
Review

Impact of concurrent genomic alterations in epidermal growth factor receptor (EGFR)-mutated lung cancer

Beatrice Gini et al. J Thorac Dis. 2020 May.

Abstract

Comprehensive characterization of the genomic landscape of epidermal growth factor receptor (EGFR)-mutated lung cancers have identified patterns of secondary mutations beyond the primary oncogenic EGFR mutation. These include concurrent pathogenic alterations affecting p53 (60-65%), RTKs (5-10%), PIK3CA/KRAS (3-23%), Wnt (5-10%), and cell cycle (7-25%) pathways as well as transcription factors such as MYC and NKX2-1 (10-15%). The majority of these co-occurring alterations were detected or enriched in samples collected from patients at resistance to tyrosine kinase inhibitor (TKI) treatment, indicating a potential functional role in driving resistance to therapy. Of note, these co-occurring tumor genomic alterations are not necessarily mutually exclusive, and evidence suggests that multiple clonal and sub-clonal cancer cell populations can co-exist and contribute to EGFR TKI resistance. Computational tools aimed to classify, track and predict the evolution of cancer clonal populations during therapy are being investigated in pre-clinical models to guide the selection of combination therapy switching strategies that may delay the development of treatment resistance. Here we review the most frequently identified tumor genomic alterations that co-occur with mutated EGFR and the evidence that these alterations effect responsiveness to EGFR TKI treatment.

Keywords: Lung cancer; mutations; oncogenes; therapy.

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Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd.2020.03.78). The series “Mechanisms of Resistance to EGFR-targeted Therapy” was commissioned by the editorial office without any funding or sponsorship. Dr. Blakely reports grants from Astrazeneca, grants from Takeda, grants from Novartis, grants from Mirati, grants from Spectrum, grants from Roche, personal fees from Revolution Medicines, personal fees from Foundation Medicine, outside the submitted work. The other authors have no other conflicts of interest to declare.

Figures

Figure 1
Figure 1
Classification of concurrent genomic alterations in EGFR-mutated NSCLC. (A) Most frequently co-occurring pathways altered in EGFR-mutated NSCLC are highlighted in the pie chart (not necessarily mutually exclusive), which can impact the efficacy of EGFR-targeted therapy. (B) A pathway-centric classification of tumor genomic co-alterations could guide the selection of combination therapy approaches (118). (C) Real-time monitoring of tumor clonal evolution through liquid biopsies in conjunction with mathematical modeling may inform combination therapy treatment schedules and switching strategies (hypothetical clonal evolution shown) (119). EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; TF, transcription factors.
See this image and copyright information in PMC

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