Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-MET, in experimental models of anaplastic large-cell lymphoma

Department of Cancer Biology, Pfizer Global Research and Development, La Jolla Laboratories, 10724 Science Center Drive, La Jolla, CA 92121, USA.
Molecular Cancer Therapeutics (Impact Factor: 6.11). 12/2007; 6(12 Pt 1):3314-22. DOI: 10.1158/1535-7163.MCT-07-0365
Source: PubMed

ABSTRACT A t(2;5) chromosomal translocation resulting in expression of an oncogenic kinase fusion protein known as nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) has been implicated in the pathogenesis of anaplastic large-cell lymphoma (ALCL). PF-2341066 was recently identified as a p.o. bioavailable, small-molecule inhibitor of the catalytic activity of c-Met kinase and the NPM-ALK fusion protein. PF-2341066 also potently inhibited NPM-ALK phosphorylation in Karpas299 or SU-DHL-1 ALCL cells (mean IC50 value, 24 nmol/L). In biochemical and cellular screens, PF-2341066 was shown to be selective for c-Met and ALK at pharmacologically relevant concentrations across a panel of > 120 diverse kinases. PF-2341066 potently inhibited cell proliferation, which was associated with G(1)-S-phase cell cycle arrest and induction of apoptosis in ALK-positive ALCL cells IC50 values, similar to 30 nmol/L) but not ALK-negative lymphoma cells. The induction of apoptosis was confirmed using terminal deoxyribonucleotide transferase-mediated nick-end labeling and Annexin V staining IC50 values, 25-50 nmol/L). P.o. administration of PF-2341066 to severe combined immunodeficient-Beige mice bearing Karpas299 ALCL tumor xenografts resulted in dose-dependent antitumor efficacy with complete regression of all tumors at the 100 mg/kg/d dose within 15 days of initial compound administration. A strong correlation was observed between antitumor response and inhibition of NPM-ALK phosphorylation and induction of apoptosis in tumor tissue. In addition, inhibition of key NPM-ALK signaling mediators, including phospholipase C-gamma, signal transducers and activators of transcription 3, extracellular signal-regulated kinases, and Akt by PF-2341066 were observed at concentrations or dose levels, which correlated with inhibition of NPM-ALK phosphorylation and function. Collectively, these data illustrate the potential clinical utility of inhibitors of NPM-ALK in treatment of patients with ALK-positive ALCL.

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    • "While only 3–5% of NSCLC tumors are ALK-rearrangement-positive [1] [2] [4], this translates into a considerable number of patients affected worldwide. Crizotinib (XALKORI; Pfizer Inc., New York, NY, USA) is an inhibitor of ALK, MET, and ROS1 [5] [6] [7]. Crizotinib gained approval in the US for the treatment of adults with ALK-positive advanced NSCLC within 4 years of the discovery of the importance of ALK rearrangement and has subsequently been approved "
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    ABSTRACT: Within 4 years of the discovery of anaplastic lymphoma kinase (ALK) rearrangements in non-small cell lung cancer (NSCLC), the ALK inhibitor crizotinib gained US and European approval for the treatment of advanced ALK-positive NSCLC. This was due to the striking response data observed with crizotinib in phase I and II trials in patients with ALK-positive NSCLC, as well as the favorable tolerability and safety profile observed. Recently published phase III data established crizotinib as the new standard of care in the second-line setting for this NSCLC molecular subset. A consequence of such rapid approval, however, is the limited clinical experience and relative paucity of information concerning optimal therapy management. In this review, we discuss the development of crizotinib and the clinical relevance of its safety profile, examining crizotinib-associated adverse events in detail and making specific management recommendations. Crizotinib-associated adverse events were mostly mild to moderate in severity in clinical studies, and appropriate monitoring and supportive therapies are considered effective in avoiding the need for dose interruption or reduction in most cases. Therapy management of patients following disease progression on crizotinib is also discussed. Based on available clinical data, it is evident that patients may have prolonged benefit from crizotinib after Response Evaluation Criteria in Solid Tumors-defined disease progression, and crizotinib should be continued for as long as the patient derives benefit.
    Lung Cancer 12/2014; 87(2). DOI:10.1016/j.lungcan.2014.12.010 · 3.74 Impact Factor
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    • "Currently crizotinib is the “drug of choice” for the NSCLCs [49,11,129]. The clinical response rates with crizotinib and the newer ALK inhibitors are roughly 30% more effective than conventional chemotherapeutic treatments [122-128,138-145]. Thus, although ALK-rearrangement targeted treatments offer a better treatment regimen, advanced ALK-rearranged NSCLC still carries a poor prognosis. "
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    ABSTRACT: The anaplastic lymphoma tyrosine kinase (ALK) gene was first described as a driver mutation in anaplastic non-Hodgkin's lymphoma. Dysregulated ALK expression is now an identified driver mutation in nearly twenty different human malignancies, including 4-9% of non-small cell lung cancers (NSCLC). The tyrosine kinase inhibitor crizotinib is more effective than standard chemotherapeutic agents in treating ALK positive NSCLC, making molecular diagnostic testing for dysregulated ALK expression a necessary step in identifying optimal treatment modalities. Here we review ALKmediated signal transduction pathways and compare the molecular protocols used to identify dysregulated ALK expression in NSCLC. We also discuss the use of crizotinib and second generation ALK tyrosine kinase inhibitors in the treatment of ALK positive NSCLC, and the known mechanisms of crizotinib resistance in NSCLC.
    Genes & cancer 04/2014; 5(1-2):1-14.
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    • "Crizotinib, the first dual ALK/MET inhibitor that entered clinical trials, has recently been approved for the treatment of locally advanced or metastatic ALK-rearranged NSCLC (Camidge et al. 2012; Christensen et al. 2007). In addition, recently published results of a phase 1 trial in children show that seven out of nine children with recurrent or refractory ALCL experienced a complete response following crizotinib monotherapy (Mosse et al. 2013). "
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    ABSTRACT: Crizotinib, 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. ALK+ 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. cDNA 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. Resistance 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.
    Journal of Cancer Research and Clinical Oncology 02/2014; 140(4). DOI:10.1007/s00432-014-1589-3 · 3.01 Impact Factor
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