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Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitors.

ABSTRACT: Aberrant forms of the anaplastic lymphoma kinase (ALK) have been implicated in the pathogenesis of multiple human cancers, where ALK represents a rational therapeutic target in these settings. In this study, we report the identification and biological characterization of X-376 and X-396, two potent and highly specific ALK small molecule tyrosine kinase inhibitors (TKIs). In Ambit kinome screens, cell growth inhibition studies, and surrogate kinase assays, X-376 and X-396 were more potent inhibitors of ALK but less potent inhibitors of MET compared to PF-02341066 (PF-1066), an ALK/MET dual TKI currently in clinical trials. Both X-376 and X-396 displayed potent antitumor activity in vivo with favorable pharmacokinetic and toxicity profiles. Similar levels of drug sensitivity were displayed by the three most common ALK fusion proteins in lung cancer (EML4-ALK variants E13;A20, E20;A20, and E6b;A20) as well as a KIF5B-ALK fusion protein. Moreover, X-396 could potently inhibit ALK kinases engineered with two point mutations associated with acquired resistance to PF-1066, L1196M, and C1156Y, when engineered into an E13;A20 fusion variant. Finally, X-396 displayed synergistic growth inhibitory activity when combined with the mTOR inhibitor rapamycin. Our findings offer preclinical proof-of-concept for use of these novel agents to improve therapeutic outcomes of patients with mutant ALK-driven malignancies.

SUBMITTER: Lovly CM

PROVIDER: S-EPMC3138877 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitors.

Lovly Christine M CM Heuckmann Johannes M JM de Stanchina Elisa E Chen Heidi H Thomas Roman K RK Liang Chris C Pao William W

Cancer research 20110525 14

Aberrant forms of the anaplastic lymphoma kinase (ALK) have been implicated in the pathogenesis of multiple human cancers, where ALK represents a rational therapeutic target in these settings. In this study, we report the identification and biological characterization of X-376 and X-396, two potent and highly specific ALK small molecule tyrosine kinase inhibitors (TKIs). In Ambit kinome screens, cell growth inhibition studies, and surrogate kinase assays, X-376 and X-396 were more potent inhibit ...[more]

PMID: 21613408

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Project description:IntroductionThis study explored the use, safety, and efficacy of initial use of an ALK-inhibiting targeted therapy (ALK tyrosine kinase inhibitor [TKI]) in patients with ALK-rearranged NSCLC in a population-based, real-world clinical population within the province of Alberta, Canada.MethodsDemographic, clinical, treatment, and outcome data of the patients with advanced or metastatic ALK-rearranged NSCLC receiving their first ALK TKI between 2014 and 2019 were included in the analysis.ResultsA total of 92 patients with ALK-rearranged NSCLC treated with ALK TKI (78% crizotinib, 22% alectinib) were identified. In the ALK-rearranged cohort, 1-year survival rate was 73% and median overall survival (OS) and progression-free survival (PFS) were 48.5 months and 17.0 months, respectively. An objective response rate of 49% was observed, and adverse events were reported in 70% of the patients, primarily of low grade (84%). Case-matched comparison to patients with ALK-wildtype disease treated with cytotoxic chemotherapy revealed the benefit of ALK TKI in the context of an ALK rearrangement (ALK-rearranged versus ALK-wildtype) (median post-treatment initiation OS: 46.8 versus 14.2 mo, p < 0.001). Outcomes, measured from the time of ALK TKI initiation, differed by Eastern Cooperative Oncology Group (ECOG) (ECOG < 2 versus ECOG ≥ 2) (median OS: not reached versus 6.8 mo, p < 0.001; median PFS 17.6 versus 7.4 mo, p = 0.02), disease presentation (relapsed versus de novo) (median PFS: 30.8 versus 15.0 mo, p = 0.04), and brain metastasis onset (brain metastases development during ALK TKI versus baseline brain metastases) (not reached versus 12.8 mo, p = 0.04).ConclusionsClinical trials have firmly established that ALK TKIs are safe, well tolerated, and effective; these findings reveal that their impact in a real-world setting is just as profound. The availability and use of ALK TKI therapies contribute to the impressive gains in survival experienced by contemporary patients with ALK-rearranged disease, rendering patients with this oncodriven form of NSCLC among the longest surviving patients with lung cancer.

Project description:IntroductionAnaplastic lymphoma kinase (ALK) fusion mutation is more common in younger and never-smoking lung cancer patients. The association of smoking and ALK-tyrosine kinase inhibitors (TKIs) on overall survival (OS) of treatment-naïve ALK-positive advanced lung adenocarcinoma remains unclear in real-world.MethodsThis retrospective study evaluated all 33170 lung adenocarcinoma patients registered in the National Taiwan Cancer Registry from 2017 to 2019, of whom 9575 advanced stage patients had ALK mutation data.ResultsAmong the 9575 patients, 650 (6.8%) patients had ALK mutation with the median follow-up survival time 30.97 months (median age, 62 years; 125 [19.2%] were aged ≥75 years; 357 (54.9%) females; 179 (27.5) smokers, 461 (70.9%) never-smokers, 10 (1.5%) with unknown smoking status; and 544 (83.7%) with first-line ALK-TKI treatment). Overall, of 535 patients with known smoking status who received first-line ALK-TKI treatment, never-smokers and smokers had a median OS of 40.7 months (95% confidence interval (CI), 33.1-47.2 months) and 23.5 months (95% CI, 11.5-35.5 months) (P=0.015), respectively. Among never-smokers, those who received first-line ALK-TKI treatment had a median OS of 40.7 months (95% CI, 22.7-57.8 months), while those ALK-TKI not as first-line treatment had a median OS of 31.7 months (95% CI, 15.2-42.8 months) (P=0.23). In smokers, the median OS for these patients was 23.5 months (95% CI, 11.5-35.5 months) and 15.6 months (95% CI, 10.2-21.1 months) (P=0.026), respectively.Conclusions and relevanceFor patients with treatment-naïve advanced lung adenocarcinoma, the ALK test should be performed irrespective of smoking status and age. Smokers had shorter median OS than never-smokers among treatment-naïve-ALK-positive patients with first-line ALK-TKI treatment. Furthermore, smokers not receiving first-line ALK-TKI treatment had inferior OS. Further investigations for the first-line treatment of ALK-positive smoking advanced lung adenocarcinoma patients are needed.

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Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitors.

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Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitors.

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