STEM-18. THE c-Jun N-TERMINAL KINASE (JNK) IS A CRUCIAL COMPONENT OF MAINTENANCE IN GLIOBLASTOMA STEM-LIKE CELLS. (5th November 2018)

• Record Type: Journal Article
• Authors: Maria Acanda de la Rocha, Arlet; Rodriguez-Silva, Monica; Gonzalez-Arias, Sergio; W. Chambers, Jeremy
• Is Part Of: Neuro-oncology. Volume 20(2018)Supplement 6
• Page Start: vi247
• Page End: vi247
• Publication Date: 2018-11-05
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy148.1025
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Glioblastoma (GBM)is the most common malignant primary brain tumors in adults, and despite established therapeutic approaches, the prognosis remains bleak. The cellular heterogeneity within GBM is one of the major causes of poor patient outcomes, whereby GBM cancer stem-like cells (GSC) drive therapeutic resistance. Compelling evidence suggests that GSCs play a major role in initiation, progression, and recurrence of GBM; therefore, there is an urgent need to identify novel therapeutic approaches that targets GSCs. c-Jun N-terminal Kinase (JNK) signaling is chronically altered in several tumors, including GBM. Therefore, defining the functional role of JNK in GSCs is critical to understanding GBM pathophysiology and developing efficacious therapies against this recalcitrant population. In this study, we examined the impact of our potent, brain-penetrant pan-JNK inhibitors (Kamenecka et al., 2010) on cell proliferation, viability, neurosphere formation and migration capacity of GSCs, and compared the novel JNK inhibitors to SP600125, a widely-used JNK inhibitor with poor brain penetrance and selectivity. Our results show that inhibition of JNK using these novel compounds decreased cell viability, proliferation, migration, and neurosphere formation capacity of GSCs to a greater extent than SP600125. The use of pan-JNK inhibitors compared to SP600125 decreased the levels of c-Jun and phospho-c-Jun, a JNK target, in GSCs, illustrating the potency of these novel inhibitors. Interestingly, inhibition of JNK with our novel compounds ultimately induced caspases 3 and 7 indicating that the compounds initiate apoptosis mechanism GSCs. Small molecule inhibitors with good brain penetrance that decrease cell proliferation, migration, and viability in GSCs, offers a novel therapeutic strategy to eliminate GSCs from tumors by primed them for apoptosis. Kamenecka T, et al. (2010) Synthesis, biological evaluation, X-ray structure, and pharmacokinetics of aminopyrimidine c-jun-N-terminal kinase (JNK) inhibitors. J Med Chem 53:419–31.