Resistance to Targeted Agents Used to Treat Paediatric ALK-Positive ALCL.
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ABSTRACT:
SUBMITTER: Hare L
PROVIDER: S-EPMC8656581 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Anaplastic Large Cell Lymphoma (ALCL) is a clinical and biological heterogeneous disease including systemic ALK positive and ALK negative entities. Whereas ALK positive ALCLs are molecularly characterized and readily diagnosed, specific immunophenotypic or genetic features to define ALK negative ALCL are missing, and their distinction from other T-cell non-Hodgkin lymphomas (T-NHLs) can be controversial. In recent years, great advances have been made in dissecting the heterogeneity of ALK negative ALCLs and in providing new diagnostic and treatment options for these patients. A new revision of the World Health Organization (WHO) classification promoted ALK negative ALCL to a definite entity that includes cytogenetic subsets with prognostic implications. However, a further understanding of the genetic landscape of ALK negative ALCL is required to dictate more effective therapeutic strategies specifically tailored for each subgroup of patients.
| S-EPMC5392347 | biostudies-literature
Project description:Activating JAK and STAT mutations were discovered in many T-cell malignancies including ALK- anaplastic large cell lymphomas (ALCL). However, such mutations often occur in a minority of patients. To investigate the clinical application of targeting Janus Kinase (JAK) for ALK- ALCL, we treated ALK- cell lines of different histologic origins with JAK inhibitors. Interestingly, most exogenous cytokine independent cell lines responded to JAK inhibition regardless of JAK mutation status. JAK inhibitor sensitivity correlated with STAT3 phosphorylation status of tumor cells. Employing retroviral shRNA knockdown, we demonstrated that these JAK inhibitor sensitive cells were dependent on both JAK1 and STAT3 for survival. JAK1 and STAT3 gain-of-function mutations were found in some but not all JAK inhibitor sensitive cells. Moreover, the mutations alone could not explain the JAK1/STAT3 dependency as wild-type JAK1 or STAT3 was sufficient to promote cell survival in the cells that had either JAK1or STAT3 mutations. To investigate whether other mechanisms were involved, we knocked down upstream receptors GP130 or IL-2Rγ. Knockdown of GP130 or IL-2Rγ induced cell death in select JAK inhibitor sensitive cells. High levels of cytokine expression including IL-6 were demonstrated in cell lines as well as in primary ALK- ALCL tumors. Finally, ruxolitinib, a JAK1/2 inhibitor, was effective in vivo in a xenograft ALK- ALCL model. Our data suggest cytokine receptor signaling was required for tumor cell survival in diverse forms of ALK- ALCL even in the presence of JAK1/STAT3 mutations. Therefore, JAK-inhibitor therapy might benefit patients with ALK- ALCL that are pSTAT3+.
2017-08-22 | GSE96048 | GEO
Project description:Peripheral T-cell lymphomas (PTCL) are a heterogeneous, and often aggressive group of non-Hodgkin lymphomas. Recent advances in the molecular and genetic characterization of PTCLs have helped to delineate differences and similarities between the various subtypes, and the JAK/STAT pathway has been found to play an important oncogenic role. Here, we aimed to characterize the JAK/STAT pathway in PTCL subtypes and investigate whether the activation of the pathway correlates with the frequency of STAT gene mutations. Patient samples from AITL (n = 30), ALCL (n = 21) and PTCL-NOS (n = 12) cases were sequenced for STAT3, STAT5B, JAK1, JAK3, and RHOA mutations using amplicon sequencing and stained immunohistochemically for pSTAT3, pMAPK, and pAKT. We discovered STAT3 mutations in 13% of AITL, 13% of ALK+ ALCL, 38% of ALK- ALCL and 17% of PTCL-NOS cases. However, no STAT5B mutations were found and JAK mutations were only present in ALK- ALCL (15%). Concurrent mutations were found in all subgroups except ALK+ ALCL where STAT3 mutations were always seen alone. High pY-STAT3 expression was observed especially in AITL and ALCL samples. When studying JAK-STAT pathway mutations, pY-STAT3 expression was highest in PTCLs harboring either JAK1 or STAT3 mutations and CD30+ phenotype representing primarily ALK- ALCLs. Further investigation is needed to elucidate the molecular mechanisms of JAK-STAT pathway activation in PTCL.
| S-EPMC7140109 | biostudies-literature
Project description:Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase expressed at early stages of normal development and in various cancers including ALK-positive anaplastic large cell lymphoma (ALK+ ALCL), in which it is the main therapeutic target. ALK tyrosine kinase inhibitors (ALK TKIs) have greatly improved the prognosis of ALK+ALCL patients, but the emergence of drug resistance is inevitable and limits the applicability of these drugs. Although various mechanisms of resistance have been elucidated, the problem persists and there have been relatively few relevant clinical studies. This review describes research progress on ALK+ ALCL including the application and development of new therapies, especially in relation to drug resistance. We also propose potential treatment strategies based on current knowledge to inform the design of future clinical trials.
| S-EPMC8862178 | biostudies-literature
Project description:Simple Summary ALK+ anaplastic large cell lymphoma (ALK+ ALCL) is a distinct type of aggressive non-Hodgkin lymphoma of T-cell origin, which is characterized by overexpression and activation of ALK kinase due to chromosomal translocations of the gene. The most frequent chromosomal aberration is the t(2;5) resulting in the NPM-ALK chimeric protein, which exerts its oncogenic functions through activation of multiple oncogenic pathways. Exosomes, the best characterized type of extracellular vesicles, are secreted from the tumor cells, thus transferring signals to other cells that uptake exosomes. In this study, we demonstrate that ALK+ ALCL cells secrete exosomes that carry critical molecules of ALK signaling, which can be taken up by other cells with significant biologic effects including functional interactions with tumor microenvironment cells, which may contribute to tumor aggressiveness and possibly resistance to treatment. Abstract The oncogenic pathways activated by the NPM-ALK chimeric kinase of ALK+ anaplastic large cell lymphoma (ALCL) are well characterized; however, the potential interactions of ALK signaling with the microenvironment are not yet known. Here we report that ALK+ ALCL-derived exosomes contain critical components of ALK signaling as well as CD30, and that exosome uptake by lymphoid cells led to increased proliferation and expression of critical antiapoptotic proteins by the recipient cells. The bone marrow fibroblasts highly uptake ALK+ ALCL-derived exosomes and acquire a cancer-associated fibroblast (CAF) phenotype. Moreover, exosome-mediated activation of stromal cells altered the cytokine profile of the microenvironment. These interactions may contribute to tumor aggressiveness and possibly resistance to treatment.
| S-EPMC9221431 | biostudies-literature
Project description:The discovery of an echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene led to improved clinical outcomes in patients with lung cancer after the development of the first ALK-targeting agent, crizotinib. Some second-generation ALK tyrosine kinase inhibitors (TKIs), which might be more potent than crizotinib or effective on crizotinib-resistant patients, have been developed. Although these ALK-TKIs show an excellent response initially, most patients eventually acquire resistance. Therefore, careful consideration of the resistance mechanisms might lead to superior therapeutic strategies. Here, we summarize the history of ALK-TKIs and their underlying resistance mechanisms in both the preclinical and clinical settings. In addition, we discuss potential future treatment strategies in ALK-TKI-naïve and -resistant patients with lung cancer harboring the EML4-ALK fusion gene.
| S-EPMC4491683 | biostudies-literature
Project description:Purpose Advanced anaplastic lymphoma kinase ( ALK) fusion-positive non-small-cell lung cancers (NSCLCs) are effectively treated with ALK tyrosine kinase inhibitors (TKIs). However, clinical outcomes in these patients vary, and the benefit of TKIs is limited as a result of acquired resistance. Emerging data suggest that the ALK fusion variant may affect clinical outcome, but the molecular basis for this association is unknown. Patients and Methods We identified 129 patients with ALK-positive NSCLC with known ALK variants. ALK resistance mutations and clinical outcomes on ALK TKIs were retrospectively evaluated according to ALK variant. A Foundation Medicine data set of 577 patients with ALK-positive NSCLC was also examined. Results The most frequent ALK variants were EML4-ALK variant 1 in 55 patients (43%) and variant 3 in 51 patients (40%). We analyzed 77 tumor biopsy specimens from patients with variants 1 and 3 who had progressed on an ALK TKI. ALK resistance mutations were significantly more common in variant 3 than in variant 1 (57% v 30%; P = .023). In particular, ALK G1202R was more common in variant 3 than in variant 1 (32% v 0%; P < .001). Analysis of the Foundation Medicine database revealed similar associations of variant 3 with ALK resistance mutation and with G1202R ( P = .010 and .015, respectively). Among patients treated with the third-generation ALK TKI lorlatinib, variant 3 was associated with a significantly longer progression-free survival than variant 1 (hazard ratio, 0.31; 95% CI, 0.12 to 0.79; P = .011). Conclusion Specific ALK variants may be associated with the development of ALK resistance mutations, particularly G1202R, and provide a molecular link between variant and clinical outcome. ALK variant thus represents a potentially important factor in the selection of next-generation ALK inhibitors.
| S-EPMC5903999 | biostudies-literature
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.
| S-EPMC3949014 | biostudies-literature
Project description:Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by the oncogenic anaplastic lymphoma kinase (ALK), accounting for approximately 15% of all paediatric non-Hodgkin lymphoma. Patients with central nervous system (CNS) relapse are particularly difficult to treat with a 3-year overall survival of 49% and a median survival of 23.5 months. The second-generation ALK inhibitor brigatinib shows superior penetration of the blood-brain barrier unlike the first-generation drug crizotinib and has shown promising results in ALK+ non-small-cell lung cancer. However, the benefits of brigatinib in treating aggressive paediatric ALK+ ALCL are largely unknown. We established a patient-derived xenograft (PDX) resource from ALK+ ALCL patients at or before CNS relapse serving as models to facilitate the development of future therapies. We show in vivo that brigatinib is effective in inducing the remission of PDX models of crizotinib-resistant (ALK C1156Y, TP53 loss) ALCL and furthermore that it is superior to crizotinib as a second-line approach to the treatment of a standard chemotherapy relapsed/refractory ALCL PDX pointing to brigatinib as a future therapeutic option.
| S-EPMC10952693 | biostudies-literature
Project description:Non-small cell lung carcinoma (NSCLC) is the major cause of cancer-associated mortality. Identification of rearrangements in anaplastic lymphoma kinase (ALK) gene is an effective instrument for more effective targeted therapy of NSCLC using ALK inhibitors dramatically raising progression-free survival in the ALK-mutated group of patients. However, the tumors frequently develop resistance to ALK inhibitors. We describe here a case of 48 y.o. male patient with ALK-positive NSCLC who was clinically managed for 6.5 years from the diagnosis. The tumor was surgically resected, but 8 months later multiple brain metastases were discovered. The patient started receiving platinum-based chemotherapy and then was enrolled in a clinical trial of second-generation ALK inhibitor ceritinib, which resulted in a 21 months stabilization. Following disease relapse, the patient was successfully managed for 33 months with different lines of chemo- and local ablative therapies. Chemotherapy regimens, including off-label combination of crizotinib + bevacizumab + docetaxel, were selected using the cancer transcriptome data-guided bioinformatical decision support system Oncobox. These therapies led to additional stabilization for 22 months. Survival of our patient after developing resistance to ALK inhibitor was longer for 16 months than previously reported average survival for such cases. This case shows that transcriptomic-guided sequential personalized prescription of targeted therapies can be effective in terms of survival and quality of life in ALK-mutated NSCLC.
| S-EPMC6803543 | biostudies-literature