Mechanisms and management of 3rdgeneration EGFRTKI resistance in advanced nonsmall cell lung cancer (Review).
Int J Oncol
; 59(5)2021 Nov.
Article
en En
| MEDLINE
| ID: mdl-34558640
ABSTRACT
Targeted therapy with epidermal growth factor receptor (EGFR)tyrosine kinase inhibitors (TKIs) is a standard modality of the 1stline treatments for patients with advanced EGFRmutated nonsmall cell lung cancer (NSCLC), and substantially improves their prognosis. However, EGFR T790M mutation is the primary mechanism of 1st and 2ndgeneration EGFRTKI resistance. Osimertinib is a representative of the 3rdgeneration EGFRTKIs that target T790M mutation, and has satisfactory efficacy in the treatment of T790Mpositive NSCLC with disease progression following use of 1st or 2ndgeneration EGFRTKIs. Other 3rdgeneration EGFRTKIs, such as abivertinib, rociletinib, nazartinib, olmutinib and alflutinib, are also at various stages of development. However, the occurrence of acquired resistance is inevitable, and the mechanisms of 3rdgeneration EGFRTKI resistance are complex and incompletely understood. Genomic studies in tissue and liquid biopsies of resistant patients reveal multiple candidate pathways. The present review summarizes the recent findings in mechanisms of resistance to 3rdgeneration EGFRTKIs in advanced NSCLC, and provides possible strategies to overcome this resistance. The mechanisms of acquired resistance mainly include an altered EGFR signaling pathway (EGFR tertiary mutations and amplification), activation of aberrant bypassing pathways (hepatocyte growth factor receptor amplification, human epidermal growth factor receptor 2 amplification and aberrant insulinlike growth factor 1 receptor activation), downstream pathway activation (RAS/RAF/MEK/ERK and PI3K/AKT/mTOR) and histological/phenotypic transformations (SCLC transformation and epithelialmesenchymal transition). The combination of targeted therapies is a promising strategy to treat osimertinibresistant patients, and multiple clinical studies on novel combined therapies are ongoing.
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1
Banco de datos:
MEDLINE
Asunto principal:
Carcinoma de Pulmón de Células no Pequeñas
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Inhibidores de Proteínas Quinasas
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Receptores ErbB
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Neoplasias Pulmonares
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Año:
2021
Tipo del documento:
Article