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C. Hoareau-Aveilla et al.
NPM-ALK+ ALCL is a rare disease which accounts for about 1-2% of adult non-Hodgkin lymphomas (NHL) and 10-15% of childhood NHL. The prognosis of NPM-ALK+ ALCL is better than that of other T-cell lymphomas. Overall, patients with NPM-ALK+ ALCL who are resistant to primary chemotherapy or who relapse early have the worst prognosis.4,45 We checked the CCNE1, E2F3 and CDK6 overexpression in a cohort of NPM-ALK+ primary ALCL samples obtained from chemotherapy-naive patients at diagnosis. As aberrant growth control is a hall- mark of cancer cells, we hypothesized that altered CCNE1, E2F3 and CDK6 expression in NPM-ALK+ patients could affect their response to treatment. Using a NPM-ALK+ cohort, including patients who had experi- enced early relapse after chemotherapy, we show that the three G1-S regulators together could predict treatment outcome in pediatric patients.
CDK6 protein is a member of the cyclin-dependent kinase family, which includes CDK4, with a 71% shared amino acid identity. These homologs are ubiquitously expressed and have largely overlapping functions. In mam- malian cells, cell cycle is regulated by CDK4 and CDK6 in early G1 phase through interactions with cyclins D1, D2 and D3. Cyclin D/CDK4 and cyclin D/CDK6 complexes induce phosphorylation of the retinoblastoma protein (Rb) and the release of E2F3 transcription factor from RB-E2F3 complexes. Cell-cycle components, such as CDK4 and CDK6, are frequently altered in human cancer, reflecting the deregulated growth of transformed cells. In B-cell lym- phoid malignancies, DNA hypermethylation-mediated epigenetic silencing of the tumor suppressors miR-124a and miR-29 results in an upregulation of their target CDK6.46 Downregulation of CDK6 was observed follow- ing introduction of miR-29a mimics into T-cell acute lym- phoblastic leukemia Jurkat cells.47 CDK6 has also been implicated in thymic lymphoma formation in a transgenic mouse model.48 Moreover, Kollmann et al. have observed that NPM-ALK– transgenic mice lacking CDK6 expression developed disease with a significantly prolonged latency.44 At the same time, in a NOD/SCID xenograft human mul- tiple myeloma model, palbociclib, a newly developed small-molecule inhibitor specific to CDK4 and CDK6, can enhance the killing of myeloma cells by dexamethasone.49 In addition, palbociclib inhibits CDK4/6 activity according to the activation status of cycling primary bone marrow
myeloma cells freshly isolated from both new and relapsed patients.49 A phase II study has shown that pro- gression-free survival was doubled with palbociclib plus standard hormone therapy in advanced hormone receptor- positive, HER2-negative breast cancer.32 Taken together, these findings provide the grounds for new therapeutic strategies in NPM-ALK+ ALCL either targeting the epige- netic regulation of miRNAs and/or directly targeting the CDK6 pathway. We have previously reported that hypomethylating drugs may benefit NPM-ALK+ patients.17 Bonvini et al. previously described the effect of flavopiri- dol, a pan-CDK inhibitor, on NPM-ALK+ ALCL cells.50 In the present study, as a proof of concept, we have present- ed in vitro data showing that palbociclib can be the first promising and specific inhibitor for therapeutic targeting of Cdk4/6 in NPM-ALK+ lymphoma cells. Our work also provides a rationale for targeting ALK+ ALCL progression with palbociclib. Indeed, it could be possible to achieve greater synergy by combining palbociclib with other cyto- toxic agents or anti-ALK tyrosine kinase inhibitor such as crizotinib, recently approved for the treatment of metasta- tic and late-stage ALK-rearranged non-small-cell lung can- cers (NSCLC). In summary, these findings suggest that CDK4/CDK6 inhibitors could be novel candidates for mechanism-defined combination therapy in ALK+ lym- phomas and possibly other ALK+-cell cancers including a proportion of NSCLC.
Acknowledgments
This work is dedicated to CHA: «A winner is a dreamer who never gives up (Nelson Mandela)». English proofreading was performed by EnPro Language Solutions (www.enprols.fr) and Greenland scientific proofreading.
Funding
This work was supported by grants from the “Ligue contre le Cancer”, Fondation ARC pour la Recherche sur le Cancer” (FM), and INCa (projet PAIR Lymphomes) (LL). CHA and AC were supported by a fellowship from the “Labex TOUCAN / Laboratoire d’excellence Toulouse Cancer”. For their technical assistance, the authors thank M. Tosolini (Pôle Technologique du CRCT – Plateau Bioinformatique INSERM-UMR1037); F. Capilla and C. Salon at the histology facility and the staff of the zootechnie Langlade, INSERM/UPS-US006/CREFRE (Toulouse, France).
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