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Anaplastic lymphoma kinase L1198F and G1201E mutations identified in anaplastic thyroid cancer patients are not ligand-independent.

ABSTRACT: Activating mutations in full length anaplastic lymphoma kinase (ALK) have been reported in neuroblastoma and in anaplastic thyroid cancer. ALK-L1198F and ALK-G1201E mutations were originally identified in anaplastic thyroid cancer (ATC) and characterized as constitutively activating mutations. In this study, we employed in vitro cell culture assays together with biochemical and in vivo Drosophila analyses to characterize their sensitivity to either activation by the FAM150A (AUG-?) and FAM150B (AUG-?) ALK ligands or inhibition by ALK inhibitors. Here we report that neither ALK-L1198F nor ALK-G1201E mutations result in ligand independent gain-of-function (GOF) activity in either in vitro biochemical analysis or the various model systems employed. ALK-L1198F is activated by the FAM150 (AUG) ligands and its ligand-dependant activity is similar to the wild type full length ALK receptor. ALK-G1201E is only very weakly activated by the FAM150 (AUG) ligands, most likely due to impaired protein stability. We conclude that neither ALK-L1198F nor ALK-G1201E displays ligand independent kinase activity, with ALK-L1198F belonging to the class of ligand dependent ALK mutations which are not constitutively active but that responds to ligand activation, while the ALK-G1201E mutation generates an unstable receptor with very low levels of kinase activity.

SUBMITTER: Guan J

PROVIDER: S-EPMC5355286 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Anaplastic lymphoma kinase L1198F and G1201E mutations identified in anaplastic thyroid cancer patients are not ligand-independent.

Guan Jikui J Wolfstetter Georg G Siaw Joachim J Chand Damini D Hugosson Fredrik F Palmer Ruth H RH Hallberg Bengt B

Oncotarget 20170201 7

Activating mutations in full length anaplastic lymphoma kinase (ALK) have been reported in neuroblastoma and in anaplastic thyroid cancer. ALK-L1198F and ALK-G1201E mutations were originally identified in anaplastic thyroid cancer (ATC) and characterized as constitutively activating mutations. In this study, we employed in vitro cell culture assays together with biochemical and in vivo Drosophila analyses to characterize their sensitivity to either activation by the FAM150A (AUG-β) and FAM150B ( ...[more]

PMID: 28030793

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Project description:Background Tyrosine kinase inhibitors (TKIs) significantly improve clinical outcomes in patients with non-small cell lung cancer due to anaplastic lymphoma kinase (ALK) gene rearrangement. However, the rate of relapse with TKIs is high owing to the development of resistance mutations during treatment. Repeated biopsies during disease progression are crucial for elucidating the molecular mechanisms underlying the development of resistance to ALK inhibitors. Analysis of cell-free DNA (cfDNA) obtained from plasma is a novel approach for tumor genotyping. Methods In this mixed prospective and retrospective observational cohort study, we investigated the clinical feasibility of continuous quantitative monitoring of ALK-acquired mutations in plasma obtained from patients with ALK+ non-small cell lung cancer by using a highly sensitive and specific droplet digital polymerase chain reaction (ddPCR) assay. We enrolled nine patients, including three treatment-naïve patients recently diagnosed with ALK+ non-small cell lung cancer via tissue biopsy and expected to receive ALK TKIs and six patients already receiving ALK TKIs. Plasma samples were collected from these patients every 3 months. cfDNA was extracted from 66 samples during the study period, and 10 ALK mutations were simultaneously evaluated. Results The numbers of samples showing the G1202R, C1156Y, G1269A, F1174L, T1151ins, and I1171T mutations were 32, 16, 5, 4, 1, and 1, respectively. The L1196M, L1152R, V1180L, and S1206Y mutations were not detected. Correlation analyses between progression-free survival and the time from treatment initiation (or treatment modification) to the detection of resistance mutations revealed that although resistance mutations may occur before a drug change becomes necessary, there is a duration during which the disease does not progress. Conclusions Our findings suggest that real-time quantitative monitoring of ALK resistance mutations during the response period could provide a time course of changes while acquiring resistance mutations. This information would be beneficial for designing an appropriate treatment strategy.

Project description:BACKGROUND:We previously noted that among atomic bomb survivors (ABS), the relative frequency of cases of adult papillary thyroid cancer (PTC) with chromosomal rearrangements (mainly RET/PTC) was significantly greater in those with relatively higher radiation exposure than those with lower radiation exposure. In contrast, the frequency of PTC cases with point mutations (mainly BRAF(V600E)) was significantly lower in patients with relatively higher radiation exposure than those with lower radiation exposure. We also found that among ABS, the frequency of PTC cases with no detectable gene alterations in RET, neurotrophic tyrosine kinase receptor 1 (NTRK1), BRAF, or RAS was significantly higher in patients with relatively higher radiation exposure than those with lower radiation exposure. However, in ABS with PTC, the relationship between the presence of the anaplastic lymphoma kinase (ALK) gene fused with other gene partners and radiation exposure has received little study. In this study, we tested the hypothesis that the relative frequency of rearranged ALK in ABS with PTC, and with no detectable gene alterations in RET, NTRK1, BRAF, or RAS, would be greater in those having relatively higher radiation exposures. METHODS:The 105 subjects in the study were drawn from the Life Span Study cohort of ABS of Hiroshima and Nagasaki who were diagnosed with PTC between 1956 and 1993. Seventy-nine were exposed (>0 mGy), and 26 were not exposed to A-bomb radiation. In the 25 ABS with PTC, and with no detectable gene alterations in RET, NTRK1, BRAF, or RAS, we examined archival, formalin-fixed, paraffin-embedded PTC specimens for rearrangement of ALK using reverse transcription-polymerase chain reaction and 5' rapid amplification of cDNA ends (5' RACE). RESULTS:We found rearranged ALK in 10 of 19 radiation-exposed PTC cases, but none among 6 patients with PTC with no radiation exposure. In addition, solid/trabecular-like architecture in PTC was closely associated with ALK rearrangements, being observed in 6 of 10 PTC cases with ALK rearrangements versus 2 of 15 cases with no ALK rearrangements. The six radiation-exposed cases of PTC harboring both ALK rearrangements and solid/trabecular-like architecture were associated with higher radiation doses and younger ages at the time of the A-bombing and at diagnosis compared to the other 19 PTC with no detectable gene alterations. CONCLUSION:Our findings suggest that ALK rearrangements are involved in the development of radiation-induced adult-onset PTC.

Project description:Lung cancer still represents the leading cause of cancer-related mortality. However, the recent advent of tyrosine kinase inhibitors (TKI), pioneering drugs against targetable mutations, have dramatically improved prognosis of advanced non-small cell lung cancer (NSCLC) patients. Anaplastic lymphoma kinase (ALK) gene rearrangements, identified in 3–7% of NSCLC cases, reflects in the constitutive activation of downstream signalling pathways, stimulating tumour cell proliferation, differentiation and survival. To accurately detect the wide spectrum of ALK rearrangements, the introduction of innovative techniques, like reverse transcriptase polymerase chain reaction (RT-PCR) or next generation sequencing (NGS) now allows for a more precise detection of variants and a more objective reading assessment, compared to the traditional diagnostic approaches. In some occasions, these new tools may dynamically monitor tumor evolution and even guide the choice of the most appropriate ALK inhibitor. In fact, among ALK TKIs available, crizotinib was the first to receive FDA accelerate approval for ALK rearranged NSCLC patients. Notwithstanding its response rate, ranging from 57% to 74%, the majority of patients progress within the first year of drug administration, due to acquired resistance. Both ALK-dependent and independent mechanisms of acquired resistance to TKIs have been identified. If the activation of multiple bypass signaling pathways constitutes the most common ALK-independent mechanism of resistance and one of the most difficult to overcome, ALK-dependent escape strategy mainly consists of mutations in the kinase domain, where the type of mutation largely depends on the TKI administered. Second and third generation TKIs are now available and are demonstrating high systemic and central nervous system (CNS) efficacy in clinical trials. Even though appropriate timing and sequencing of these compounds are still unclear, the large number of ALK inhibitors is now a precious resource aiming to prolong progression-free survival (PFS) and finally overall survival (OS). Here Authors provide an overview of the current approaches in the clinical management of advanced NSCLC patients harboring ALK rearrangement and discuss future perspectives to address current issues, highlighting the perception that ALK-rearranged advanced NSCLC patients benefit from maintained ALK inhibition for as long as possible.

Dataset Information

Anaplastic lymphoma kinase L1198F and G1201E mutations identified in anaplastic thyroid cancer patients are not ligand-independent.

Publications

Anaplastic lymphoma kinase L1198F and G1201E mutations identified in anaplastic thyroid cancer patients are not ligand-independent.

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