Prediction of ALK mutations mediating ALK-TKIs resistance and drug re-purposing to overcome the resistance

Published on Jan 17, 2019in EBioMedicine8.143
路 DOI :10.1016/J.EBIOM.2019.01.019
Koutaroh Okada4
Estimated H-index: 4
(JFCR: Japanese Foundation for Cancer Research),
Mitsugu Araki13
Estimated H-index: 13
(Kyoto University)
+ 14 AuthorsRyohei Katayama35
Estimated H-index: 35
(JFCR: Japanese Foundation for Cancer Research)
Sources
Abstract
Abstract Background Alectinib 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. Methods We 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). Findings We 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 IC50 value of several ALK-TKIs to single- or compound-mutated EML4-ALK expressing Ba/F3 cells and in recapitulating the tendency of the binding affinity reduction by double mutations found in this study. Computational simulation revealed that ALK-L1256F single mutant conferred resistance to lorlatinib but increased the sensitivity to alectinib. Interpretation We 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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#2Jessica J. Lin (Harvard University)H-Index: 25
Last. Alice T. Shaw (Harvard University)H-Index: 96
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The cornerstone of treatment for advanced ALK-positive lung cancer is sequential therapy with increasingly potent and selective ALK inhibitors. The third-generation ALK inhibitor lorlatinib has demonstrated clinical activity in patients who failed previous ALK inhibitors. To define the spectrum of ALK mutations that confer lorlatinib resistance, we performed accelerated mutagenesis screening of Ba/F3 cells expressing EML4-ALK. Under comparable conditions, ENU mutagenesis generated numerous crizo...
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#2Hiroshi NokiharaH-Index: 51
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Summary Background Alectinib, a potent, highly selective, CNS-active inhibitor of anaplastic lymphoma kinase (ALK), showed promising efficacy and tolerability in the single-arm phase 1/2 AF-001JP trial in Japanese patients with ALK -positive non-small-cell lung cancer. Given those promising results, we did a phase 3 trial to directly compare the efficacy and safety of alectinib and crizotinib. Methods J-ALEX was a randomised, open-label, phase 3 trial that recruited ALK inhibitor-naive Japanese ...
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BackgroundAlectinib, a highly selective inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system (CNS) efficacy in the treatment of ALK-positive non鈥搒mall-cell lung cancer (NSCLC). We investigated alectinib as compared with crizotinib in patients with previously untreated, advanced ALK-positive NSCLC, including those with asymptomatic CNS disease. MethodsIn a randomized, open-label, phase 3 trial, we randomly assigned 303 patients with previously untreated, ad...
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Abstract Anaplastic lymphoma kinase is expressed in two-thirds of the anaplastic large-cell lymphomas as an NPM-ALK fusion protein. Physiological ALK is a receptor protein-tyrosine kinase within the insulin receptor superfamily of proteins that participates in nervous system development. The EML4-ALK fusion protein and four other ALK-fusion proteins play a fundamental role in the development in about 5% of non-small cell lung cancers. The amino-terminal portions of the ALK fusion proteins result...
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The efficacy of anaplastic lymphoma kinase (ALK) positive non-small-cell lung cancer (NSCLC) treatment with small molecule inhibitors is greatly challenged by acquired resistance. A recent study reported the newest generation inhibitor resistant mutation L1198F led to the resensitization to crizotinib, which is the first Food and Drug Administration (FDA) approved drug for the treatment of ALK-positive NSCLC. It is of great importance to understand how this extremely rare event occurred for the ...
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Accurate prediction of binding affinities of drug candidates to their targets remains challenging because of protein flexibility in solution. Conformational flexibility of the ATP-binding site in the CDK2 and ERK2 kinases was identified using molecular dynamics simulations. The binding free energy (螖G) of twenty-four ATP-competitive inhibitors toward these kinases was assessed using an alchemical free energy perturbation method, MP-CAFEE. However, large calculation errors of 2鈥3 kcal/mol were ob...
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#2Rana Anjum (ARIAD Pharmaceuticals, Inc.)H-Index: 9
Last. Victor M. Rivera (ARIAD Pharmaceuticals, Inc.)H-Index: 63
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Purpose: Non鈥搒mall cell lung cancers (NSCLCs) harboring ALK gene rearrangements (ALK + ) typically become resistant to the first-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) crizotinib through development of secondary resistance mutations in ALK or disease progression in the brain. Mutations that confer resistance to second-generation ALK TKIs ceritinib and alectinib have also been identified. Here, we report the structure and first comprehensive preclinical evalua...
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#1Guolin ZhangH-Index: 10
#2Hannah Scarborough (Anschutz Medical Campus)H-Index: 6
Last. Eric B. HauraH-Index: 70
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Patients with lung cancers harboring anaplastic lymphoma kinase (ALK) gene fusions benefit from treatment with ALK inhibitors, but acquired resistance inevitably arises. A better understanding of proximal ALK signaling mechanisms may identify sensitizers to ALK inhibitors that disrupt the balance between prosurvival and proapoptotic effector signals. Using affinity purification coupled with mass spectrometry in an ALK fusion lung cancer cell line (H3122), we generated an ALK signaling network an...
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#1Justin F. Gainor (Harvard University)H-Index: 63
#2Leila Dardaei (Harvard University)H-Index: 15
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Advanced, anaplastic lymphoma kinase (ALK)-positive lung cancer is currently treated with the first-generation ALK inhibitor crizotinib followed by more potent, second-generation ALK inhibitors (e.g., ceritinib, alectinib) upon progression. Second-generation inhibitors are generally effective even in the absence of crizotinib-resistant ALK mutations, likely reflecting incomplete inhibition of ALK by crizotinib in many cases. Herein, we analyzed 103 repeat biopsies from ALK-positive patients prog...
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#2Shuangying Liu (ARIAD Pharmaceuticals, Inc.)H-Index: 11
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In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within the ALK kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candid...
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Despite impressive and durable responses, non-small cell lung cancer (NSCLC) patients treated with anaplastic lymphoma kinase inhibitors (ALK-Is) ultimately progress due to development of resistance. Here, we have evaluated the clinical utility of circulating tumor DNA (ctDNA) profiling by next-generation sequencing (NGS) upon disease progression. We collected26 plasma and two cerebrospinal fluid samples from 24 advanced ALK-positive NSCLC patients at disease progression to an ALK-I. These sampl...
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#2Yuichi KumakiH-Index: 3
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Of the 80 solid tumor cases in which liquid biopsy (LB) was performed using Guardant360 in the PROFILE study, nine were lung cancer cases. Here, we review three cases in which LB was useful in diagnosing ALK fusion-positive lung cancer, selecting sequential ALK-tyrosine kinase inhibitors, confirming uncommon EGFR mutations, and receiving biomarker-compatible therapy.
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To date, there have been no head-to-head randomized controlled trials (RCTs) comparing the safety and efficacy of lorlatinib and alectinib in anaplastic lymphoma kinase (ALK) rearrangement-positive (ALK-p) ALK-inhibitor鈥抧aive advanced non-small cell lung cancer (NSCLC). We performed a network meta-analysis comparing six treatment arms (lorlatinib, brigatinib, alectinib, ceritinib, crizotinib, and platinum-based chemotherapy) in overall participants and in Asian and non-Asian subgroups. Primary e...
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#1Shiruyeh Schokrpur (UCSD: University of California, San Diego)H-Index: 7
Introduction: Alectinib is a second-generation inhibitor of anaplastic lymphoma kinase (ALK) and RET. Phase III clinical trials have established its superiority to crizotinib in the first-line ALK inhibitor-naive setting. Studies also support its use over chemotherapy in the post-crizotinib setting. It is currently one of several FDA- and EMA-approved ALK inhibitors, and it is listed as a preferred initial therapy for treatment-naive ALK-positive non-small cell lung cancer (NSCLC).Areas covered:...
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