ArticleEBioMedicine2019
Prediction of ALK mutations mediating ALK-TKIs resistance and drug re-purposing to overcome the resistance.
Article in EBioMedicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 81 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
81 citing papers in PubMed, 125 citations in OpenAlex.
- Updated overall survival and circulating tumor DNA analysis of ensartinib for crizotinib-refractory ALK-positive NSCLC from a phase II study.Cancer communications (London, England) · 2024Trial
- Low-Concentration Enhancement Effect: Enabling Sensitive Detection of EML4-ALK Variants via Multiplex RT-MIRA.Journal of clinical laboratory analysis · 2026Article
- Review
- ALK rearrangements and resistance mutations in non-small cell lung cancer: molecular mechanisms and therapeutic implications.Cancer chemotherapy and pharmacology · 2026Review
- Multi-omics integration in deciphering non-small cell lung cancer drug resistance: current status, challenges, and future prospects.Hereditas · 2026Review
- Sustained Complete Response to Brigatinib in a Young Patient With ALK-Positive NSCLC Harboring I1171N Mutation Post-Alectinib Resistance.Case reports in oncological medicine · 2026Article
- Central Nervous System Progression in Patients Receiving ALK-Targeted Central Nervous System-Penetrable Tyrosine Kinase Inhibitors: Treatment Patterns and Outcomes.JTO clinical and research reports · 2025Article
- Spectrum of Resistance Mechanisms to ALK TKIs in NSCLC: Largest Single-Center Experience from India.South Asian journal of cancer · 2025Article
- Preclinical Prediction of Resistance Mutations and Proposal of Sequential Treatment Strategies for ALK-positive Lung Cancer Using Next-generation ALK Inhibitors.Pharmaceutical research · 2025Article
- Anti-EGFR therapy can overcome acquired resistance to the third-generation ALK-tyrosine kinase inhibitor lorlatinib mediated by activation of EGFR.Acta pharmacologica Sinica · 2025Article
- Advances in molecular pathology and therapy of non-small cell lung cancer.Signal transduction and targeted therapy · 2025Review
- Molecular tumor board: molecularly adjusted therapy upon identification and functional validation of a novel ALK resistance mutation in a case of lung adenocarcinoma.The oncologist · 2025Article
- Case Report: Treatment response of SQSTM1-ALK fusion lung adenocarcinoma to multiple ALK inhibitors.Frontiers in pharmacology · 2025Article
- Global research trends on ALK-TKIs in non-small cell lung cancer: a bibliometric analysis.Frontiers in pharmacology · 2025Article
- New advances in understanding the mechanisms and treatment challenges of ALK-targeted therapy resistance in lung cancer.Cancer drug resistance (Alhambra, Calif.) · 2025Review
- Case Report: Successful late-line pralsetinib treatment in an ALK-rearranged lung adenocarcinoma patient with KIF5B-RET fusion resistant to alectinib.Frontiers in genetics · 2025Article
- Mechanisms of Resistance to ALK Inhibitors and Corresponding Treatment Strategies in Lung Cancer.International journal of general medicine · 2025Review
- [Research Progress of ALK Activation Pattern Changes and Targeted Therapy in Advanced Lung Cancer].Zhongguo fei ai za zhi = Chinese journal of lung cancer · 2024Review
- Mechanisms of resistance to tyrosine kinase inhibitor-targeted therapy and overcoming strategies.MedComm · 2024Review
- TKI type switching overcomes ROS1 L2086F in ROS1 fusion-positive cancers.NPJ precision oncology · 2024Article
21 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
17 authors at 6 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundAlectinib has shown a greater efficacy to ALK-rearranged non-small-cell lung cancers in first-line setting; however, most patients relapse due to acquired resistance, such as secondary mutations in ALK including I1171N and G1202R. Although ceritinib or lorlatinib was shown to be effective to these resistant mutants, further resistance often emerges due to ALK-compound mutations in relapse patients following the use of ceritinib or lorlatinib. However, the drug for overcoming resistance has not been established yet.
methodsWe established lorlatinib-resistant cells harboring ALK-I1171N or -G1202R compound mutations by performing ENU mutagenesis screening or using an in vivo mouse model. We performed drug screening to overcome the lorlatinib-resistant ALK-compound mutations. To evaluate these resistances in silico, we developed a modified computational molecular dynamic simulation (MP-CAFEE).
findingsWe identified 14 lorlatinib-resistant ALK-compound mutants, including several mutants that were recently discovered in lorlatinib-resistant patients. Some of these compound mutants were found to be sensitive to early generation ALK-TKIs and several BCR-ABL inhibitors. Using our original computational simulation, we succeeded in demonstrating a clear linear correlation between binding free energy and in vitro experimental IC
interpretationWe discovered lorlatinib-resistant multiple ALK-compound mutations and an L1256F single mutation as well as the potential therapeutic strategies for these ALK mutations. Our original computational simulation to calculate the binding affinity may be applicable for predicting resistant mutations and for overcoming drug resistance in silico. FUND: This work was mainly supported by MEXT/JSPS KAKENHI Grants and AMED Grants.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.