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Ref Type Journal Article
PMID (32558295)
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
Vol 12
Issue 7
Date 2020 Jul 07
URL
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.

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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