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Impact of concurrent genomic alterations in epidermal growth factor receptor (EGFR)-mutated lung cancer
Beatrice Gini1,2, Nicholas Thomas1,2, Collin M Blakely1,2
1Department of Medicine, University of California, San Francisco, California, USA.
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.
Insights
Secondary mutations in EGFR-mutated lung cancer, affecting pathways like p53 and cell cycle, often emerge during tyrosine kinase inhibitor (TKI) resistance. Understanding these genomic alterations is key to overcoming treatment resistance.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Epidermal growth factor receptor (EGFR)-mutated lung cancers are often treated with tyrosine kinase inhibitors (TKIs).
- Secondary genetic alterations frequently co-occur with the primary oncogenic EGFR mutation.
- These co-occurring alterations are implicated in the development of resistance to EGFR-targeted therapies.
Purpose of the Study:
- To review frequently identified tumor genomic alterations co-occurring with mutated EGFR.
- To examine the evidence linking these alterations to EGFR TKI treatment resistance.
- To discuss the role of clonal evolution in EGFR TKI resistance.
Main Methods:
- Comprehensive genomic characterization of EGFR-mutated lung cancers.
- Analysis of co-occurring mutations in pathways such as p53, RTKs, PIK3CA/KRAS, Wnt, and cell cycle.
- Review of pre-clinical models investigating computational tools for tracking cancer clonal populations.
Main Results:
- Common co-occurring alterations include mutations in p53 (60-65%), RTKs (5-10%), PIK3CA/KRAS (3-23%), Wnt (5-10%), cell cycle pathways (7-25%), and transcription factors MYC and NKX2-1 (10-15%).
- The majority of these alterations are enriched in patients resistant to TKI treatment.
- Multiple co-existing cancer cell populations (clonal and sub-clonal) can contribute to EGFR TKI resistance.
Conclusions:
- Co-occurring genomic alterations play a significant role in driving resistance to EGFR TKI therapy.
- Understanding the genomic landscape and clonal evolution is crucial for developing strategies to overcome treatment resistance.
- Further research into computational tools and combination therapies is needed to delay or prevent resistance.
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