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New pan-ALK inhibitor-resistant EML4::ALK mutations detected by liquid biopsy in lung cancer patients.

ABSTRACT: ALK and ROS1 fusions are effectively targeted by tyrosine kinase inhibitors (TKIs), however patients inevitably relapse after an initial response, often due to kinase domain mutations. We investigated circulating DNA from TKI-relapsed NSCLC patients by deep-sequencing. New EML4::ALK substitutions, L1198R, C1237Y and L1196P, were identified in the plasma of NSCLC ALK patients and characterized in a Ba/F3 cell model. Variants C1237Y and L1196P demonstrated pan-inhibitor resistance across 5 clinical and 2 investigational TKIs.

SUBMITTER: Villa M

PROVIDER: S-EPMC10918084 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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New pan-ALK inhibitor-resistant EML4::ALK mutations detected by liquid biopsy in lung cancer patients.

Villa Matteo M Malighetti Federica F Sala Elisa E Sharma Geeta G GG Arosio Giulia G Gemelli Maria M Manfroni Chiara C Fontana Diletta D Cordani Nicoletta N Meneveri Raffaella R Zambon Alfonso A Piazza Rocco R Pagni Fabio F Cortinovis Diego D Mologni Luca L

NPJ precision oncology 20240306 1

ALK and ROS1 fusions are effectively targeted by tyrosine kinase inhibitors (TKIs), however patients inevitably relapse after an initial response, often due to kinase domain mutations. We investigated circulating DNA from TKI-relapsed NSCLC patients by deep-sequencing. New EML4::ALK substitutions, L1198R, C1237Y and L1196P, were identified in the plasma of NSCLC ALK patients and characterized in a Ba/F3 cell model. Variants C1237Y and L1196P demonstrated pan-inhibitor resistance across 5 clinica ...[more]

PMID: 38448512

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