Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors

By Adi F. Gazdar. Oncogene, 2009

1,000 citations recorded by the source corpus.

The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), gefitinib and erlotinib, are reversible competitive inhibitors of the tyrosine kinase domain of EGFR that bind to its adenosine-5′ triphosphate-binding site. Somatic activating mutations of the EGFR gene, increased gene copy number and certain clinical and pathological features have been associated with dramatic tumor responses and favorable clinical outcomes with these agents in patients with non-small-cell lung cancer (NSCLC). The specific types of activating mutations that confer sensitivity to EGFR TKIs are present in the tyrosine kinase (TK) domain of the EGFR gene. Exon 19 deletion mutations and the single-point substitution mutation L858R in exon 21 are the most frequent in NSCLC and are termed ‘classical’ mutations. The NSCLC tumors insensitive to EGFR TKIs include those driven by the KRAS and MET oncogenes. Most patients who initially respond to gefitinib and erlotinib eventually become resistant and experience progressive disease. The point mutation T790M accounts for about one half of these cases of acquired resistance. Various second-generation EGFR TKIs are currently being evaluated and may have the potential to overcome T790M-mediated resistance by virtue of their irreversible inhibition of the receptor TK domain.

Subfields: Molecular Biology, Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/cb6d1d41ef979a54257b639b47a5244291f84183

How researchers see this paper

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In Molecular Biology

1. R. Huang
2. Tetsuo Noda
3. Yoshio Miki
4. T. Tan
5. S. Mori
6. Q. H. Miow
7. J. P. Thiery
8. S. Lippman

In Oncology

1. R. Huang
2. Tetsuo Noda
3. Yoshio Miki
4. T. Tan
5. S. Mori
6. Q. H. Miow
7. J. P. Thiery
8. Jie Yang

In Pulmonary and Respiratory Medicine

1. J. P. Thiery
2. R. Huang
3. Tetsuo Noda
4. L. Sequist
5. Yoshio Miki
6. T. Tan
7. S. Lippman
8. S. Mori

Citations in the corpus

• Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. (2013, background): “T790M mutations may already be present in EGFR TKI treatment– naive patients,(26,27) and the presence of a detectable de novo T790M mutation predicts for shorter PFS with EGFR TKIs.(26,28,29) Afatinib had in vitro activity against the T790M variant(10) and improved PFS compared with placebo in a ran”
• Epithelial-mesenchymal transition spectrum quantification and its efficacy in deciphering survival and drug responses of cancer patients (2014, positive): “On the other hand, cell lines harbouring the secondary gatekeeper EGFR-T790M mutation, which confers resistance to EGFR inhibitors (Gazdar, 2009), were more Mes (EMT score = +0.”
• EMERGING BIOLOGICAL PRINCIPLES OF METASTASIS (2017, neutral): “…resistant clones may emerge in primary tumors and metastatic lesions, as has been observed, for example, in ER+ breast cancer patients receiving hormone therapy (Alluri et al., 2014) and patients with EGFR-mutant non-small-cell lung cancer treated with targeted kinase inhibitors (Gazdar, 2009).”
• PTEN loss in the continuum of common cancers, rare syndromes and mouse models (2011, neutral): “Mutant epidermal growth factor receptor ( EGFR ) is a frequent driving mutation in lung cancer in never-smoker”
• Targeting the Mitogen-Activated Protein Kinase RAS-RAF Signaling Pathway in Cancer Therapy (2012, background): “Notably, thyroid tumours based on their histotype origins may present different types of RAS alterations withK-RASmutations mainly associated with papillary thyroid carcinoma (PTC) and N-RAS with follicular thyroid carcinomas, follicular variant PTCs, and poorly differentiated thyroid carcinomas [26”