A study published in Sci Transl Med (2012) investigates the mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. The research identifies secondary mutations in the ALK tyrosine kinase domain, including new resistance mutations in the solvent-exposed region of the ATP-binding pocket, and ALK fusion gene amplification in 22% of 18 patients with crizotinib-resistant lung cancers. Next-generation ALK inhibitors showed varying potencies against these resistance mutations. Additionally, aberrant activation of other kinases, including KIT amplification and increased autophosphorylation of EGFR, was observed in drug-resistant tumors. In some patients, multiple resistance mechanisms developed simultaneously. The study also found that mutations such as L1196M, G1202R, and S1206Y in the ALK domain confer resistance to crizotinib, with S1206Y conferring the least resistance. These mutations are located in the solvent-exposed region of the kinase domain, potentially reducing crizotinib's affinity for the mutant ALK. The 1151Tins mutation, located in the N-terminal loop of helix C, is predicted to be farther from the crizotinib-binding site and may affect ALK's affinity for ATP. Next-generation ALK inhibitors, such as NVP-TAE684, CH5424802, and ASP-3026, showed varying degrees of potency against these resistance mutations. Hsp90 inhibitors, such as 17-AAG, were also effective against resistant ALK mutants, suggesting they could be used to overcome crizotinib resistance. The study also found that EGFR activation can mediate crizotinib resistance, with increased EGFR activation observed in some resistant tumors. However, EGFR activation alone may not fully explain the resistance phenotype, and combined ALK and EGFR inhibition may not be as effective as crizotinib in treating crizotinib-sensitive disease. KIT amplification and stromal SCF were also identified as potential resistance mechanisms. In some cases, multiple resistance mechanisms co-existed, highlighting the complexity of crizotinib resistance. The study suggests that combination therapies targeting multiple resistance mechanisms may be necessary to overcome crizotinib resistance. The findings emphasize the importance of identifying the precise resistance mechanisms in each patient to tailor therapeutic strategies and improve clinical outcomes.A study published in Sci Transl Med (2012) investigates the mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. The research identifies secondary mutations in the ALK tyrosine kinase domain, including new resistance mutations in the solvent-exposed region of the ATP-binding pocket, and ALK fusion gene amplification in 22% of 18 patients with crizotinib-resistant lung cancers. Next-generation ALK inhibitors showed varying potencies against these resistance mutations. Additionally, aberrant activation of other kinases, including KIT amplification and increased autophosphorylation of EGFR, was observed in drug-resistant tumors. In some patients, multiple resistance mechanisms developed simultaneously. The study also found that mutations such as L1196M, G1202R, and S1206Y in the ALK domain confer resistance to crizotinib, with S1206Y conferring the least resistance. These mutations are located in the solvent-exposed region of the kinase domain, potentially reducing crizotinib's affinity for the mutant ALK. The 1151Tins mutation, located in the N-terminal loop of helix C, is predicted to be farther from the crizotinib-binding site and may affect ALK's affinity for ATP. Next-generation ALK inhibitors, such as NVP-TAE684, CH5424802, and ASP-3026, showed varying degrees of potency against these resistance mutations. Hsp90 inhibitors, such as 17-AAG, were also effective against resistant ALK mutants, suggesting they could be used to overcome crizotinib resistance. The study also found that EGFR activation can mediate crizotinib resistance, with increased EGFR activation observed in some resistant tumors. However, EGFR activation alone may not fully explain the resistance phenotype, and combined ALK and EGFR inhibition may not be as effective as crizotinib in treating crizotinib-sensitive disease. KIT amplification and stromal SCF were also identified as potential resistance mechanisms. In some cases, multiple resistance mechanisms co-existed, highlighting the complexity of crizotinib resistance. The study suggests that combination therapies targeting multiple resistance mechanisms may be necessary to overcome crizotinib resistance. The findings emphasize the importance of identifying the precise resistance mechanisms in each patient to tailor therapeutic strategies and improve clinical outcomes.