Analysis of Tumor Heterogeneity Through AXL Activation in Primary Resistance to EGFR Tyrosine Kinase Inhibitors

Ryota Nakamura, MD; Hiroyuki Fujii, MD; Tadaaki Yamada, MD, PhD; Yohei Matsui, MD; Takeshi Yaoi, MS; Mizuki Honda, MD; Noriyuki Tanaka, MD, PhD; Aya Miyagawa-Hayashino, MD, PhD; Akihiro Yoshimura, MD, PhD; Kenji Morimoto, MD, PhD; Masahiro Iwasaku, MD, PhD; Shinsaku Tokuda, MD, PhD; Young Hak Kim, MD, PhD; Eiichi Konishi, MD, PhD; Kyoko Itoh, MD, PhD; Koichi Takayama, MD, PhD

JTO Clinical and Research Reports (Jun 2023)

Analysis of Tumor Heterogeneity Through AXL Activation in Primary Resistance to EGFR Tyrosine Kinase Inhibitors

Ryota Nakamura, MD,
Hiroyuki Fujii, MD,
Tadaaki Yamada, MD, PhD,
Yohei Matsui, MD,
Takeshi Yaoi, MS,
Mizuki Honda, MD,
Noriyuki Tanaka, MD, PhD,
Aya Miyagawa-Hayashino, MD, PhD,
Akihiro Yoshimura, MD, PhD,
Kenji Morimoto, MD, PhD,
Masahiro Iwasaku, MD, PhD,
Shinsaku Tokuda, MD, PhD,
Young Hak Kim, MD, PhD,
Eiichi Konishi, MD, PhD,
Kyoko Itoh, MD, PhD,
Koichi Takayama, MD, PhD

Affiliations

Ryota Nakamura, MD: Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
Hiroyuki Fujii, MD: Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
Tadaaki Yamada, MD, PhD: Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan; Corresponding author. Address for correspondence: Tadaaki Yamada, MD, PhD, Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kamigyo-ku, Kyoto, Japan.
Yohei Matsui, MD: Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
Takeshi Yaoi, MS: Department of Pathology and Applied Neurobiology, Kyoto Prefectural University of Medicine, Kyoto, Japan
Mizuki Honda, MD: Department of Surgical Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan
Noriyuki Tanaka, MD, PhD: Department of Surgical Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan
Aya Miyagawa-Hayashino, MD, PhD: Department of Surgical Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan
Akihiro Yoshimura, MD, PhD: Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
Kenji Morimoto, MD, PhD: Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
Masahiro Iwasaku, MD, PhD: Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
Shinsaku Tokuda, MD, PhD: Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
Young Hak Kim, MD, PhD: Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
Eiichi Konishi, MD, PhD: Department of Surgical Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan
Kyoko Itoh, MD, PhD: Department of Pathology and Applied Neurobiology, Kyoto Prefectural University of Medicine, Kyoto, Japan
Koichi Takayama, MD, PhD: Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan

Journal volume & issue: Vol. 4, no. 6
p. 100525

Abstract

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Introduction: EGFR tyrosine kinase inhibitors are standard therapeutic agents for patients with advanced NSCLC harboring EGFR mutations. Nevertheless, some patients exhibit primary resistance to EGFR tyrosine kinase inhibitors in the first-line treatment setting. AXL, a member of the TYRO3, AXL, and MERTK family of receptor tyrosine kinases, is involved in primary resistance to EGFR tyrosine kinase inhibitors in EGFR-mutated NSCLC. Methods: We investigated spatial tumor heterogeneity using autopsy specimens and a patient-derived cell line from a patient with EGFR-mutated NSCLC having primary resistance to erlotinib plus ramucirumab. Results: Quantitative polymerase chain reaction analysis revealed that AXL mRNA expression differed at each metastatic site. In addition, AXL expression levels were likely to be negatively correlated with the effectiveness of erlotinib plus ramucirumab therapy. Analysis of a patient-derived cell line established from the left pleural effusion before initiation of treatment revealed that the combination of EGFR tyrosine kinase inhibitors and an AXL inhibitor remarkably inhibited cell viability and increased cell apoptosis in comparison with EGFR tyrosine kinase inhibitor monotherapy or combination therapy of these inhibitors with ramucirumab. Conclusions: Our observations suggest that AXL expression may play a critical role in the progression of spatial tumor heterogeneity and primary resistance to EGFR tyrosine kinase inhibitors in patients with EGFR-mutated NSCLC.

Published in JTO Clinical and Research Reports

ISSN: 2666-3643 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.journals.elsevier.com/jto-clinical-and-research-reports/

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