Editorial on the article entitled "brigatinib efficacy and safety in patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer in a phase I/II trial".
Editorial on the article entitled "brigatinib efficacy and safety in patients with anaplastic lymphoma kinase (<i>ALK</i>)-positive non-small cell lung cancer in a phase I/II trial".
Project description:Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor which has been implicated in numerous solid and hematologic cancers. ALK mutations are reported in about 5-7% of neuroblastoma cases but the ALK-positive percentage increases significantly in the relapsed patient population. Crizotinib, the first clinically approved ALK inhibitor for the treatment of ALK-positive lung cancer has had less dramatic responses in neuroblastoma. Here we investigate the efficacy of a second-generation ALK inhibitor, brigatinib, in a neuroblastoma setting. Employing neuroblastoma cell lines, mouse xenograft and Drosophila melanogaster model systems expressing different constitutively active ALK variants, we show clear and efficient inhibition of ALK activity by brigatinib. Similar abrogation of ALK activity was observed in vitro employing a set of different constitutively active ALK variants in biochemical assays. These results suggest that brigatinib is an effective inhibitor of ALK kinase activity in ALK addicted neuroblastoma that should be considered as a potential future therapeutic option for ALK-positive neuroblastoma patients alone or in combination with other treatments.
Project description:Oncogenic receptor tyrosine kinases including anaplastic lymphoma kinase (ALK) are implicated in numerous solid and hematologic cancers. ALK mutations are reported in an estimated 9% of neuroblastoma and recent reports indicate that the percentage of ALK-positive cases increases in the relapsed patient population. Initial clinical trial results have shown that it is difficult to inhibit growth of ALK positive neuroblastoma with crizotinib, motivating investigation of next generation ALK inhibitors with higher affinity for ALK. Here, alectinib, a potent next generation ALK inhibitor with antitumor activity was investigated in ALK-driven neuroblastoma models. Employing neuroblastoma cell lines and mouse xenografts we show a clear and efficient inhibition of ALK activity by alectinib. Inhibition of ALK activity was observed in vitro employing a set of different constitutively active ALK variants in biochemical assays. The results suggest that alectinib is an effective inhibitor of ALK kinase activity in ALK addicted neuroblastoma and should be considered as a potential future therapeutic option for ALK-positive neuroblastoma patients alone or in combination with other treatments.
Project description:The fusion of echinoderm microtubule-associated protein-like 4 with anaplastic lymphoma kinase (ALK) was identified as a transforming gene for lung cancer in 2007. This genetic rearrangement accounts for 2%-5% of non-small-cell lung cancer (NSCLC) cases, occurring predominantly in younger individuals with adenocarcinoma who are never- or light smokers. A small-molecule tyrosine-kinase inhibitor of ALK, crizotinib, was rapidly approved by the US Food and Drug Administration on the basis of its pronounced clinical activity in patients with ALK rearrangement-positive NSCLC. Next-generation ALK inhibitors, such as alectinib, LDK378, and AP26113, are also being developed in ongoing clinical trials. In addition, the improvement and validation of methods for the detection of ALK rearrangement in NSCLC patients will be key to the optimal clinical use of ALK inhibitors. We here summarize recent progress in the development of new ALK inhibitors and in the molecular diagnosis of ALK rearrangement-positive NSCLC.
Project description:Cancer cells are characterized by high genetic instability, that favors tumor relapse. The identification of the genetic causes of relapse can direct next-line therapeutic choices. As tumor tissue rebiopsy at disease progression is not always feasible, noninvasive alternative methods are being explored. Liquid biopsy is emerging as a non-invasive, easy and repeatable tool to identify specific molecular alterations and monitor disease response during treatment. The dynamic follow-up provided by this analysis can provide useful predictive information and allow prompt therapeutic actions, tailored to the genetic profile of the recurring disease, several months before radiographic relapse. Oncogenic fusion genes are particularly suited for this type of analysis. Anaplastic Lymphoma Kinase (ALK) is the dominant driver oncogene in several tumors, including Anaplastic Large-Cell Lymphoma (ALCL), Non-Small Cell Lung Cancer (NSCLC) and others. Here we review recent findings in liquid biopsy technologies, including ctDNA, CTCs, exosomes, and other markers that can be investigated from plasma samples, in ALK-positive cancers.
Project description:ALK-positive anaplastic large cell lymphoma (ALCL) represents approximately 6-7% of the mature T-cell lymphomas. This subtype contains a translocation between the ALK gene on chromosome 2 and one of several other genes that together form an oncogene. The most frequent translocation is t(2;5) which combines ALK with NPM1. This lymphoma has a median age of 34 years, is more common in males, and is in advanced stage at the time of diagnosis in most patients. ALK-positive ALCL is the most curable of the peripheral T-cell lymphomas. The CHOP regimen has been most frequently used, but results are improved with the substitution of brentuximab vedotin for vincristine (BV-CHP) and the addition of etoposide (CHOEP), with BV-CHP being favored. Salvage therapies include allogeneic or autologous bone marrow transplantation, BV, if not used as part of the primary therapy, and ALK inhibitors. The latter are very active and likely to be incorporated into the primary therapy.
Project description:We present the development of the first small molecule degraders that can induce anaplastic lymphoma kinase (ALK) degradation, including in non-small-cell lung cancer (NSCLC), anaplastic large-cell lymphoma (ALCL), and neuroblastoma (NB) cell lines. These degraders were developed through conjugation of known pyrimidine-based ALK inhibitors, TAE684 or LDK378, and the cereblon ligand pomalidomide. We demonstrate that in some cell types degrader potency is compromised by expression of drug transporter ABCB1. In addition, proteomic profiling demonstrated that these compounds also promote the degradation of additional kinases including PTK2 (FAK), Aurora A, FER, and RPS6KA1 (RSK1).
Project description:Background and objectiveWhile anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are standard of care treatment for metastatic ALK-positive non-small cell lung cancer (NSCLC), the benefit of moving ALK inhibitors to earlier disease stages is unclear. The objective of this review is to summarize the literature regarding the prevalence and prognosis of early-stage ALK-positive NSCLC and the utility of targeted therapies, immunotherapy, and chemotherapy in the neoadjuvant and adjuvant settings.MethodsWe identified the references for this narrative review through a literature search of papers about early stage ALK-positive NSCLC using PubMed and clinicaltrials.gov. Last search was run on July 3, 2022. There were no language or time frame restrictions.Key content and findingsThe incidence of oncogenic ALK alterations in early-stage NSCLC ranges from 2-7%, and ALK-positive NSCLC patients are more likely to be younger and never or light smokers. Studies on the prognostic impact of ALK in early-stage disease have had conflicting results. ALK TKIs are not approved in the neoadjuvant or adjuvant setting and there is a lack of large, randomized trial results. Several trials are currently accruing but results are not expected for several years.ConclusionsAttempts at large, randomized trials to evaluate the benefit of ALK TKIs in the adjuvant and neoadjuvant has been hampered by slow recruitment given the rarity of ALK alterations, lack of universal genetic testing, and the rapid pace of drug development. Expanded lung cancer screening recommendations, liberalization of surrogate endpoints (i.e., pathological complete response and major pathological response), growth of multicenter national clinical trials, and new diagnostic technologies (i.e., cell-free DNA liquid biopsies) provide hope of generating much needed data to definitively answer the question of the utility of ALK-directed therapies in the early-stage setting.
Project description:PurposeCrizotinib, the first FDA-approved ALK inhibitor, showed significant antitumor activity in young patients with anaplastic large-cell lymphoma (ALCL) frequently displaying ALK rearrangement. However, long-term therapeutic benefits of crizotinib are limited due to development of drug resistance. CH5424802--more potent and selective ALK inhibitor--comprises a good candidate for second-line treatment in crizotinib-relapsed patients. The aim of this study was to determine possible mechanisms of resistance to ALK inhibitors that can appear in ALCL patients.MethodsALK+ ALCL cell lines resistant to crizotinib (Karpas299CR) and to CH5424802 (Karpas299CHR) were established by long-term exposure of Karpas299 cells to these inhibitors. Next, alterations in their sensitivity to ALK, HSP90 and mTOR inhibitors were investigated by cell viability and BrdU incorporation assays and immunoblot analysis.ResultscDNA sequencing of ALK kinase domain revealed activating mutations-I1171T in Karpas299CR and F1174C in Karpas299CHR. The resistant cells displayed diminished sensitivity to structurally unrelated ALK inhibitors-crizotinib, CH5424802 and TAE684. Nevertheless, CH5424802 and TAE684 were still more potent against the resistant cells than crizotinib. Moreover, Karpas299CR and Karpas299CHR cells remained sensitive to HSP90 or mTOR inhibitors.ConclusionsResistance mediated by activating mutations in ALK kinase domain may emerge in ALCL patients during ALK inhibitors treatment. However, more potent second-generation ALK inhibitors, HSP90 or mTOR inhibitors may represent an effective therapy for relapsed ALK+ ALCL patients.