Most T790M mutations are present on the same EGFR allele as activating mutations in patients with non-small cell lung cancer.

Abstract

OBJECTIVES:

The T790M and C797S mutations of the epidermal growth factor receptor gene (EGFR) confer resistance to first- and third-generation EGFR tyrosine kinase inhibitors (TKIs), respectively, in patients with non-small cell lung cancer (NSCLC) harboring activating mutations of EGFR. C797S has been identified in cis or in trans with T790M in tumor specimens from patients who experienced treatment failure with first- and third-generation EGFR-TKIs. The allelic relation between T790M and activating mutations of EGFR has not been well characterized, however. We have now developed a digital polymerase chain reaction (dPCR)-based method for determination of the allelic relation between two types of EGFR mutation (T790M and either C797S or an activating mutation).

MATERIALS AND METHODS:

Seven clinical NSCLC specimens and two NSCLC cell lines harboring both an activating mutation and T790M were analyzed with this new method to identify the allelic relation between these EGFR mutations.

RESULTS:

The median ratio of the number of alleles positive for both an activating mutation and T790M to the number of T790M-positive alleles was 97.1% (range, 90.0-100%). Confirmatory analysis by next-generation sequencing yielded a corresponding value of 96.7% (range, 89.1-99.5%). Our dPCR method thus reliably identifies the allelic relation between two EGFR mutations in a quantitative manner.

CONCLUSIONS:

Almost all T790M mutations were detected in cis with activating mutations of EGFR regardless of the de novo or acquired status of T790M, with cancer cells harboring T790M and activating mutations on the same allele appearing to be selected and enriched during EGFR-TKI treatment.

• Authors: Noriko Hidaka, Eiji Iwama, Naoki Kubo, Taishi Harada, Kohta Miyawaki, Kentaro Tanaka, Isamu Okamoto, Eishi Baba, Koichi Akashi, Hiroyuki Sasaki, Yoichi Nakanishi
• Journal: Lung cancer (Amsterdam, Netherlands) (Lung Cancer) Vol. 108 Pg. 75-82 (06 2017) ISSN: 1872-8332 [Electronic] Ireland
• PMID: 28625653 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• ErbB Receptors

Topics

• Alleles
• Amino Acid Substitution
• Antineoplastic Agents (therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, metabolism)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (genetics)
• ErbB Receptors (genetics, metabolism)
• Exons
• Humans
• Lung Neoplasms (drug therapy, genetics, metabolism)
• Mutation
• Protein Kinase Inhibitors (therapeutic use)