Overcoming Osimertinib Resistance with AKT Inhibition in EGFRm-Driven Non-Small Cell Lung Cancer with PIK3CA/PTEN Alterations.
Clin Cancer Res
; 30(18): 4143-4154, 2024 Sep 13.
Article
en En
| MEDLINE
| ID: mdl-38630555
ABSTRACT
PURPOSE:
Osimertinib is an EGFR tyrosine kinase inhibitor indicated for the treatment of EGFR-mutated (EGFRm)-driven lung adenocarcinomas. Osimertinib significantly improves progression-free survival in first-line-treated patients with EGFRm advanced non-small cell lung cancer (NSCLC). Despite the durable disease control, the majority of patients receiving osimertinib eventually develop disease progression. EXPERIMENTALDESIGN:
ctDNA profiling analysis of on-progression plasma samples from patients treated with osimertinib in both first- (phase III, FLAURA trial) and second-line trials (phase III, AURA3 trial) revealed a high prevalence of PIK3CA/AKT/PTEN alterations. In vitro and in vivo evidence using CRISPR-engineered NSCLC cell lines and patient-derived xenograft (PDX) models supports a functional role for PIK3CA and PTEN mutations in the development of osimertinib resistance.RESULTS:
These alterations are functionally relevant as EGFRm NSCLC cells with engineered PIK3CA/AKT/PTEN alterations develop resistance to osimertinib and can be resensitized by treatment with the combination of osimertinib and the AKT inhibitor capivasertib. Moreover, xenograft and PDX in vivo models with PIK3CA/AKT/PTEN alterations display limited sensitivity to osimertinib relative to models without alterations, and in these double-mutant models, capivasertib and osimertinib combination elicits an improved antitumor effect versus osimertinib alone.CONCLUSIONS:
Together, this approach offers a potential treatment strategy for patients with EGFRm-driven NSCLC who have a suboptimal response or develop resistance to osimertinib through PIK3CA/AKT/PTEN alterations. See related commentary by Vokes et al., p. 3968.
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Acrilamidas
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Carcinoma de Pulmón de Células no Pequeñas
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Resistencia a Antineoplásicos
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Ensayos Antitumor por Modelo de Xenoinjerto
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Fosfohidrolasa PTEN
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Proteínas Proto-Oncogénicas c-akt
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Fosfatidilinositol 3-Quinasa Clase I
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Receptores ErbB
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Compuestos de Anilina
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Neoplasias Pulmonares
Límite:
Animals
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Humans
Idioma:
En
Revista:
Clin Cancer Res
/
Clin. cancer res
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Clinical cancer research
Asunto de la revista:
NEOPLASIAS
Año:
2024
Tipo del documento:
Article
País de afiliación:
Reino Unido