PIM kinases are constitutively active proto-oncogenic serine/threonine kinases that play a role in cell cycle progression, metabolism, inflammation and drug resistance. PIM kinases interact with and stabilize p53, c-Myc and parallel signaling pathway PI3K/Akt. This study evaluated PIM kinase expression in NSCLC and in response to PI3K/mTOR inhibition. It investigated a novel preclinical PI3K/mTOR/PIM inhibitor (IBL-301) in vitro and in patient-derived NSCLC tumor tissues. Western blot analysis confirmed PIM1, PIM2 and PIM3 are expressed in NSCLC cell lines and PIM1 is a marker of poor prognosis in patients with NSCLC. IBL-301 decreased PIM1, c-Myc, pBAD and p4EBP1 (Thr37/46) and peIF4B (S406) protein levels in-vitro and MAP kinase, PI3K-Akt and JAK/STAT pathways in tumor tissue explants. IBL-301 significantly decreased secreted pro-inflammatory cytokine MCP-1. Altered mRNA expression, including activated PIM kinase and c-Myc, was identified in Apitolisib resistant cells (H1975GR) by an IL-6/STAT3 pathway array and validated by Western blot. H1975GR cells were more sensitive to IBL-301 than parent cells. A miRNA array identified a dysregulated miRNA signature of PI3K/mTOR drug resistance consisting of regulators of PIM kinase and c-Myc (miR17-5p, miR19b-3p, miR20a-5p, miR15b-5p, miR203a, miR-206). Our data provides a rationale for co-targeting PIM kinase and PI3K-mTOR to improve therapeutic response in NSCLC.
Approximately 340 patients are diagnosed with renal cell cancer (RCC) in Ireland each year. Metastatic spread to the lung, lymph nodes and bones is common. Metastatic spread to the gastrointestinal tract, including the small bowel, is a rare phenomenon. Therapeutic advances have led to an improved overall survival in RCC and, as a result, unusual sites of metastatic spread are becoming more common. We present the case of a 68-year-old gentleman presenting with upper gastrointestinal bleeding as a result of metastases to the duodenum from renal cell carcinoma.
populations with a high smoking rate. Ongoing analysis of the remaining genes will be used for pathway analysis and could provide a more complete picture of the lung cancer pathogenesis.
Jährlich wird in Irland bei etwa 340 Patienten ein Nierenzellkarzinom (renal cell cancer, RCC) diagnostiziert. Häufig kommt es zu einer Metastasierung in die Lunge, Lymphknoten und Knochen. Eine Metastasierung in den Gastrointestinaltrakt, einschließlich Dünndarm, ist selten. Die Fortschritte in der Therapie haben zu einem verbesserten Gesamtüberleben bei RCC geführt, was zur Folge hat, dass Metastasen häufiger an ungewöhnlichen Lokalisationen auftreten. In der vorliegenden Arbeit stellen wir den Fall eines 68-jährigen Patienten vor, der mit einer oberen gastrointestinalen Blutung aufgrund von Duodenalmetastasen eines Nierenzellkarzinoms ins Krankenhaus kam.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.