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|Ref Type||Journal Article|
|Authors||Paliouras AR, Buzzetti M, Shi L, Donaldson IJ, Magee P, Sahoo S, Leong HS, Fassan M, Carter M, Di Leva G, Krebs MG, Blackhall F, Lovly CM, Garofalo M|
|Title||Vulnerability of drug-resistant EML4-ALK rearranged lung cancer to transcriptional inhibition.|
|Journal||EMBO molecular medicine|
|Date||2020 Jul 07|
|Abstract Text||A subset of lung adenocarcinomas is driven by the EML4-ALK translocation. Even though ALK inhibitors in the clinic lead to excellent initial responses, acquired resistance to these inhibitors due to on-target mutations or parallel pathway alterations is a major clinical challenge. Exploring these mechanisms of resistance, we found that EML4-ALK cells parental or resistant to crizotinib, ceritinib or alectinib are remarkably sensitive to inhibition of CDK7/12 with THZ1 and CDK9 with alvocidib or dinaciclib. These compounds robustly induce apoptosis through transcriptional inhibition and downregulation of anti-apoptotic genes. Importantly, alvocidib reduced tumour progression in xenograft mouse models. In summary, our study takes advantage of the transcriptional addiction hypothesis to propose a new treatment strategy for a subset of patients with acquired resistance to first-, second- and third-generation ALK inhibitors.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|EML4 - ALK||lung adenocarcinoma||predicted - sensitive||Alvocidib + Crizotinib||Preclinical - Cell culture||Actionable||In a preclinical study, Alvocidib (flavopiridol) treatment in combination with Xalkori (crizotinib) reduced viability of Xalkori (crizotinib)-resistant lung adenocarcinoma cells harboring EML4-ALK in culture, but did not result in synergistic effects (PMID: 32558295).||32558295|
|EML4 - ALK||lung adenocarcinoma||sensitive||Dinaciclib||Preclinical - Cell culture||Actionable||In a preclinical study, Dinaciclib (SCH 727965) treatment induced apoptosis, reduced viability, and inhibited proliferation in parental lung adenocarcinoma cells, and isogenic cells resistant to Xalkori (crizotinib), Zykadia (ceritinib), and Alecensa (alectinib), all harboring EML4-ALK in culture (PMID: 32558295).||32558295|
|EML4 - ALK||lung adenocarcinoma||conflicting||Lorlatinib||Preclinical - Cell line xenograft||Actionable||In a preclinical study, Xalkori (crizotinib) and Zykadia (ceritinib)-resistant lung adenocarcinoma cell lines harboring EML4-ALK demonstrated resistance to Lorbrena (lorlatinib) treatment in culture, however, in Alecensa (alectinib)-resistant cells treatment led to reduced viability, and inhibited tumor growth in the cell line xenograft model with Xalkori (crizotinib) resistance (PMID: 32558295).||32558295|
|EML4 - ALK||lung adenocarcinoma||sensitive||THZ1||Preclinical - Cell culture||Actionable||In a preclinical study, THZ1 treatment reduced viability and inhibited proliferation of parental lung adenocarcinoma, and isogenic cells resistant to Xalkori (crizotinib), Zykadia (ceritinib), and Alecensa (alectinib) cells, all harboring EML4-ALK, in culture (PMID: 32558295).||32558295|
|EML4 - ALK||lung adenocarcinoma||sensitive||Alvocidib||Preclinical - Cell line xenograft||Actionable||In a preclinical study, Alvocidib (flavopiridol) treatment induced cell cycle arrest and apoptosis, reduced viability, and inhibited proliferation in both a parental lung adenocarcinoma cell line and isogenic lung adenocarcinoma cell lines resistant to Xalkori (crizotinib), Zykadia (ceritinib), and Alecensa (alectinib), all harboring EML4-ALK, in culture, and reduced tumor growth in Xalkori (crizotinib) and Alecensa (alectinib)-resistant cell line xenograft models (PMID: 32558295).||32558295|