The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status

Abstract: Resistance to anaplastic lymphoma kinase (ALK)-targeted therapy in ALK-positive non-small cell lung cancer has been reported, with the majority of acquired resistance mechanisms relying on bypass signaling. To proactively identify resistance mechanisms in ALK-positive neuroblastoma (NB), we herein employ genome-wide CRISPR activation screens of NB cell lines treated with brigatinib or ceritinib, identifying PIM1 as a putative resistance gene, whose high expression is associated with high-risk disease and poor survival. Knockdown of PIM1 sensitizes cells of differing MYCN status to ALK inhibitors, and in patient-derived xenografts of high-risk NB harboring ALK mutations, the combination of the ALK inhibitor ceritinib and PIM1 inhibitor AZD1208 shows significantly enhanced anti-tumor efficacy relative to single agents. These data confirm that PIM1 overexpression decreases sensitivity to ALK inhibitors in NB, and suggests that combined front-line inhibition of ALK and PIM1 is a viable strategy for the treatment of ALK-positive NB independent of MYCN status

Examining the Role of Nup88 and LINC complex in Breast Cancer Metastasis

In the last 20 years, it has emerged that Nup88, a cytoplasmic non FG-repeat containing nucleoporin of the nuclear pore complex (NPCs), is over-expressed in a variety of malignant tumours. Several nucleoporins have been previously associated with cancer progression, such as Nup88 binding partners, Nup214 and Nup358/RanBP2. However, Nup88’s association to tumorigenesis is more complex. Nup88 has recently been found at the inner nuclear membrane (INM) associating with lamins, suggesting Nup88 may have additional roles at the nuclear envelope (NE). Overall, the multifaceted nature of Nup88 has sparked research into the role of NPCs and Nup88 in the progression of cancer. Throughout this project we have extended our knowledge of the contribution NE proteins play in the maintenance of nuclear architecture in a variety of breast cancer cell lines. Through western blotting, immunofluorescence, and immunohistochemical studies, significant changes were observed in the expression of the major NPC and LINC (Linker of Nucleoskeleton and Cytoskeleton) complex components, such as Nesprin-2, SUN proteins, Nup88 and lamin A/C, indicating a deregulation of the bridging complex and its associating partners in breast cancer. As a significant increase in Nup88 was detected in the triple negative breast cancer cell line MDA-MB-231, the primacy of Nup88 in influencing malignant progression via cell cycle deregulation was further examined. Our studies did not indicate a clear relationship between Nup88 overexpression, proliferation, and cancer; therefore, we focused on determining whether Nup88 played a causational or consequential role in the onset of tumorigenesis via potential association to Nesprin-2 (encoded by SYNE2). CRISPR/Cas9 lentiviral activation of SYNE2 in triple negative breast cancer cell lines reduced the levels of Nup88. These changes were accompanied by a rescue of nuclear and cellular architecture. Consequently, we hypothesize decreasing Nup88 levels in triple negative breast cancer cell lines could promote re-integration of Nesprin-2 to the NE. All together, this data suggests Nup88 plays a significant role in tumorigenesis and has the potential to become a future tumour aggressiveness biomarker

Cancers / The Role of Activator Protein-1 (AP-1) Family Members in CD30-Positive Lymphomas

The Activator Protein-1 (AP-1) transcription factor (TF) family, composed of a variety of members including c-JUN, c-FOS and ATF, is involved in mediating many biological processes such as proliferation, differentiation and cell death. Since their discovery, the role of AP-1 TFs in cancer development has been extensively analysed. Multiple in vitro and in vivo studies have highlighted the complexity of these TFs, mainly due to their cell-type specific homo- or hetero-dimerization resulting in diverse transcriptional response profiles. However, as a result of the increasing knowledge of the role of AP-1 TFs in disease, these TFs are being recognized as promising therapeutic targets for various malignancies. In this review, we focus on the impact of deregulated expression of AP-1 TFs in CD30-positive lymphomas including Classical Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma.(VLID)471545

Blocking STAT3/5 through direct or upstream kinase targeting in leukemic cutaneous T-cell lymphoma

Leukemic cutaneous T-cell lymphomas (L-CTCL) are lymphoproliferative disorders of skin-homing mature T-cells causing severe symptoms and high mortality through chronic inflammation, tissue destruction, and serious infections. Despite numerous genomic sequencing efforts, recurrent driver mutations have not been identified, but chromosomal losses and gains are frequent and dominant. We integrated genomic landscape analyses with innovative pharmacologic interference studies to identify key vulnerable nodes in L-CTCL. We detected copy number gains of loci containing the STAT3/5 oncogenes in 74% (n = 17/23) of L-CTCL, which correlated with the increased clonal T-cell count in the blood. Dual inhibition of STAT3/5 using small-molecule degraders and multi-kinase blockers abolished L-CTCL cell growth in vitro and ex vivo, whereby PAK kinase inhibition was specifically selective for L-CTCL patient cells carrying STAT3/5 gains. Importantly, the PAK inhibitor FRAx597 demonstrated encouraging anti-leukemic activity in vivo by inhibiting tumor growth and disease dissemination in intradermally xenografted mice. We conclude that STAT3/5 and PAK kinase interaction represents a new therapeutic node to be further explored in L-CTCL