New pan-ALK inhibitor-resistant EML4::ALK mutations detected by liquid biopsy in lung cancer patients.
Matteo VillaFederica MalighettiElisa SalaGeeta G SharmaGiulia ArosioMaria GemelliChiara ManfroniDiletta FontanaNicoletta CordaniRaffaella MeneveriAlfonso ZambonRocco PiazzaFabio PagniDiego Luigi CortinovisLuca MologniPublished in: NPJ precision oncology (2024)
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.
Keyphrases
- advanced non small cell lung cancer
- end stage renal disease
- ejection fraction
- newly diagnosed
- chronic kidney disease
- small cell lung cancer
- single cell
- cell death
- clinical trial
- acute myeloid leukemia
- tyrosine kinase
- oxidative stress
- genome wide
- copy number
- multiple myeloma
- circulating tumor
- reactive oxygen species
- open label
- protein kinase
- high throughput sequencing