Applying a next-generation sequencing assay targeting 145 cancer-relevant genes in 40 colorectal cancer and 24 non-small cell lung cancer formalin-fixed paraffin-embedded tissue specimens identified at least one clinically relevant genomic alteration in 59% of the samples and revealed two gene fusions, C2orf44-ALK in a colorectal cancer sample and KIF5B-RET in a lung adenocarcinoma Further screening of 561 lung adenocarcinomas identified 11 additional tumors with KIF5B-RET gene fusions (20%; 95% CI 08-31%) Cells expressing oncogenic KIF5B-RET are sensitive to multi-kinase inhibitors that inhibit RET

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Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies

Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma

New mutations and pathogenesis of myeloproliferative neoplasms.

Chronic exposure to JAK2 inhibitors leads to reactivation of downstream signalling through the formation of heterodimers between JAK2 and other JAK kinases in myeloproliferative neoplasms, which can be overcome with Hsp90 inhibitors. Mutations in JAK kinases, in particular JAK2, are frequent in some malignancies and JAK inhibitors have been trialled for example in patients with myeloproliferative neoplasms (MPNs). Here, Ross Levine and colleagues demonstrate that MPN cells can persist under conditions of chronic JAK2 inhibition, because JAK2 forms a heterodimer with other JAK kinases, leading to persistent JAK2 activation. This mode of drug 'persistence' seems to occur in patients treated with JAK2 inhibitor. Therapeutic approaches that induce JAK2 degradation may therefore be more effective than treatment with JAK2 inhibitors alone. The identification of somatic activating mutations in JAK2 (refs 1–4) and in the thrombopoietin receptor gene (MPL)5 in most patients with myeloproliferative neoplasm (MPN) led to the clinical development of JAK2 kinase inhibitors6,7. JAK2 inhibitor therapy improves MPN-associated splenomegaly and systemic symptoms but does not significantly decrease or eliminate the MPN clone in most patients with MPN. We therefore sought to characterize mechanisms by which MPN cells persist despite chronic inhibition of JAK2. Here we show that JAK2 inhibitor persistence is associated with reactivation of JAK–STAT signalling and with heterodimerization between activated JAK2 and JAK1 or TYK2, consistent with activation of JAK2 in trans by other JAK kinases. Further, this phenomenon is reversible: JAK2 inhibitor withdrawal is associated with resensitization to JAK2 kinase inhibitors and with reversible changes in JAK2 expression. We saw increased JAK2 heterodimerization and sustained JAK2 activation in cell lines, in murine models and in patients treated with JAK2 inhibitors. RNA interference and pharmacological studies show that JAK2-inhibitor-persistent cells remain dependent on JAK2 protein expression. Consequently, therapies that result in JAK2 degradation retain efficacy in persistent cells and may provide additional benefit to patients with JAK2-dependent malignancies treated with JAK2 inhibitors.

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Heterodimeric JAK–STAT activation as a mechanism of persistence to JAK2 inhibitor therapy

Recent advances in our understanding of the pathogenesis of the Philadelphia chromosome-negative myeloproliferative neoplasms, polycythaemia vera, essential thrombocythaemia and myelofibrosis have led to the identification of the mutation V617F in Janus kinase (JAK) as a potential therapeutic target. This information has prompted the development of ATP-competitive JAK2 inhibitors. Therapy with JAK2 inhibitors may induce rapid and marked reductions in spleen size and can lead to remarkable improvements in constitutional symptoms and overall quality of life. Because JAKs are involved in the pathogenesis of inflammatory and immune-mediated disorders, JAK inhibitors are also being tested in clinical trials in patients with rheumatoid arthritis and psoriasis, as well as for the treatment of other autoimmune diseases and for the prevention of allograft rejection. Preliminary results indicate that these agents hold great promise for the treatment of JAK-driven disorders.

Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond

Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells

Purpose: Bortezomib induces unfolded protein response (UPR) and endoplasmic reticulum stress, as well as exhibits clinical activity in patients with relapsed and refractory mantle cell lymphoma (MCL). Here, we determined the molecular basis of the improved in vitro and in vivo activity of the combination of the pan-histone deacetylase inhibitor panobinostat and bortezomib against human, cultured, and primary MCL cells. Experimental Design: Immunoblot analyses, reverse transcription-PCR, and immunofluorescent and electron microscopy were used to determine the effects of panobinostat on bortezomib-induced aggresome formation and endoplasmic reticulum stress in MCL cells. Results: Treatment with panobinostat induced heat shock protein 90 acetylation; depleted the levels of heat shock protein 90 client proteins, cyclin-dependent kinase 4, c-RAF, and AKT; and abrogated bortezomib-induced aggresome formation in MCL cells. Panobinostat also induced lethal UPR, associated with induction of CAAT/enhancer binding protein homologous protein (CHOP). Conversely, knockdown of CHOP attenuated panobinostat-induced cell death of MCL cells. Compared with each agent alone, cotreatment with panobinostat increased bortezomib-induced expression of CHOP and NOXA, as well as increased bortezomib-induced UPR and apoptosis of cultured and primary MCL cells. Cotreatment with panobinostat also increased bortezomib-mediated in vivo tumor growth inhibition and improved survival of mice bearing human Z138C MCL cell xenograft. Conclusion: These findings suggest that increased UPR and induction of CHOP are involved in enhanced anti-MCL activity of the combination of panobinostat and bortezomib. Clin Cancer Res; 16(19); 4742–54. ©2010 AACR.

https://clincancerres.aacrjournals.org/content/clincanres/16/19/4742.full.pdf

Role of CAAT/Enhancer Binding Protein Homologous Protein in Panobinostat-Mediated Potentiation of Bortezomib-Induced Lethal Endoplasmic Reticulum Stress in Mantle Cell Lymphoma Cells

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Erratum: Role of CAAT/enhancer binding protein homologous protein in panobinostat-mediated potentiation of bortezomib-induced lethal endoplasmic reticulum stress in mantle cell lymphoma cells (Clinical Cancer Research (2010) 16 (4742–4754) DOI: 10.1158/1078-0432.CCR-10-0529)

Andrew Savoie

Papers

Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells

Role of CAAT/Enhancer Binding Protein Homologous Protein in Panobinostat-Mediated Potentiation of Bortezomib-Induced Lethal Endoplasmic Reticulum Stress in Mantle Cell Lymphoma Cells

Erratum: Role of CAAT/enhancer binding protein homologous protein in panobinostat-mediated potentiation of bortezomib-induced lethal endoplasmic reticulum stress in mantle cell lymphoma cells (Clinical Cancer Research (2010) 16 (4742–4754) DOI: 10.1158/1078-0432.CCR-10-0529)