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Resistance mechanisms of EGFR tyrosine kinase inhibitors, in EGFR exon 20 insertion-mutant lung cancer.
Park, Siyeon; Park, Seongyeol; Kim, Tae Min; Kim, Soyeon; Koh, Jaemoon; Lim, Joonoh; Yi, Kijong; Yi, Boram; Ju, Young Seok; Kim, Miso; Keam, Bhumsuk; Kim, Jung Sun; Jeon, Yoon Kyung; Kim, Dong-Wan; Kim, Young Tae; Heo, Dae Seog.
Afiliación
  • Park S; Seoul National University Cancer Research Institute, Seoul, South Korea.
  • Park S; Inocras Inc., San Diego, CA, USA; Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
  • Kim TM; Seoul National University Cancer Research Institute, Seoul, South Korea; Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea. Electronic address: gabriel9@snu.ac.kr.
  • Kim S; Seoul National University Cancer Research Institute, Seoul, South Korea; Integrated Major in Innovative Medical Science, Seoul National University College of Medicine, Seoul, South Korea.
  • Koh J; Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea.
  • Lim J; Inocras Inc., San Diego, CA, USA; Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
  • Yi K; Inocras Inc., San Diego, CA, USA; Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
  • Yi B; Inocras Inc., San Diego, CA, USA.
  • Ju YS; Inocras Inc., San Diego, CA, USA; Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
  • Kim M; Seoul National University Cancer Research Institute, Seoul, South Korea; Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.
  • Keam B; Seoul National University Cancer Research Institute, Seoul, South Korea; Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.
  • Kim JS; Seoul National University Cancer Research Institute, Seoul, South Korea; Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.
  • Jeon YK; Seoul National University Cancer Research Institute, Seoul, South Korea; Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea.
  • Kim DW; Seoul National University Cancer Research Institute, Seoul, South Korea; Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.
  • Kim YT; Seoul National University Cancer Research Institute, Seoul, South Korea; Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, Seoul, South Korea.
  • Heo DS; Seoul National University Cancer Research Institute, Seoul, South Korea; Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.
Eur J Cancer ; 208: 114206, 2024 Sep.
Article en En | MEDLINE | ID: mdl-38981315
ABSTRACT

BACKGROUND:

Mobocertinib, an EGFR exon 20 insertion (Ex20ins)-specific tyrosine kinase inhibitor has been used for treatment of advanced/metastatic EGFR Ex20ins-mutant non-small cell lung cancer (NSCLC). However, resistance mechanisms to EGFR Ex20ins-specific inhibitors and the efficacy of subsequent amivantamab treatment is unknown.

METHODS:

To investigate resistance mechanisms, tissue and cfDNA samples were collected before treatment initiation and upon development of resistance from NSCLC patients with EGFR Ex20ins mutations received mobocertinib, poziotinib, and amivantamab treatments. Genetic alterations were analyzed using whole-genome and targeted sequencing, and in vitro resistant cell lines were generated for validation.

RESULTS:

EGFR amplification (n = 6, including 2 broad copy number gain) and EGFR secondary mutation (n = 3) were observed at the resistance of mobocertinib. One patient had both EGFR secondary mutation and high EGFR focal amplification. In vitro models harboring EGFR alterations were constructed to validate resistance mechanisms and identify overcoming strategies to resistance. Acquired EGFR-dependent alterations were found to mediate resistance to mobocertinib in patients and in vitro models. Furthermore, two of six patients who received sequential amivantamab followed by an EGFR tyrosine kinase inhibitor had MET amplification and showed partial response.

CONCLUSIONS:

Our study revealed EGFR-dependent and -independent mechanisms of mobocertinib resistance in patients with advanced EGFR Ex20ins-mutant NSCLC.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Exones / Carcinoma de Pulmón de Células no Pequeñas / Resistencia a Antineoplásicos / Receptores ErbB / Neoplasias Pulmonares Límite: Humans Idioma: En Revista: Eur J Cancer Año: 2024 Tipo del documento: Article País de afiliación: Corea del Sur Pais de publicación: Reino Unido
Texto completo
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Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Exones / Carcinoma de Pulmón de Células no Pequeñas / Resistencia a Antineoplásicos / Receptores ErbB / Neoplasias Pulmonares Límite: Humans Idioma: En Revista: Eur J Cancer Año: 2024 Tipo del documento: Article País de afiliación: Corea del Sur Pais de publicación: Reino Unido