Belizatinib is a potent inhibitor for non-small cell lung cancers driven by different variants of EML4-ALK fusion proteins carrying L1196M-mutations

Li, Pan (2022): Belizatinib is a potent inhibitor for non-small cell lung cancers driven by different variants of EML4-ALK fusion proteins carrying L1196M-mutations. Dissertation, LMU München: Medizinische Fakultät

Abstract

Structural fusions of EML4 with ALK kinase might lead to signaling abnormalities that drive NSCLC. Although approved specific ALK inhibitors have led to excellent initial responses in ALK positive NSCLC patients, acquired resistance to these inhibitors due to the occurrence of mutations is a major clinical challenge. Studies have shown that different mutations are related with unique and specific responses to certain inhibitors, and that the sensitivity of EML4-ALK fusion variants to ALK specific inhibitors varies. To investigate the response spectrum of combinations of each resistance mutation and EML4-ALK fusion gene variant (V) to different ALK specific inhibitors, individual cellular Ba/F3 models were constructed and used for ALK-TKIs screening in this thesis. Based on cell viability assays, the results gained here suggested that brigatinib might be priority recommended for G1269A and L1152R mutations, lorlatinib for C1156Y and I1171T mutations and belizatinib for G1269A and L1196M mutation. Moreover, a tendency was observed that V2 was most sensitive to ALK-TKIs, V1 and V3b had intermediate sensitivity and V3a was the least sensitive. But there were situations where drug sensitivity was not in line with the expected additive effects of mutation- and variant- dependent sensitivities, which indicated the necessity of taking both variants and mutations into consideration. Notably, belizatinib, a drug in development, was approximately twenty times as potent as lorlatinib for ALK-L1196M in all types of fusion variants. The promising efficacy of belizatinib against L1196M mutation of EML4-ALK were also proven by molecular dynamics simulations. In conclusion, the results of this study provided sensitivity spectra with clinical confirmed EML4-ALK mutation-fusion combinations to nine ALK-TKIs, offered a possible optimal sequence of ALK-TKIs for treating ALK-positive patients developing resistance mutations during therapy and suggested belizatinib as a promising possible targeted inhibitor for the L1196M mutation of EML4-ALK in NSCLC.

Abstract

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 30. November 2022
• 1. Bericht­erstatter:in: Jung, Andreas