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P90-RSK as a synthetic lethal target in pancreatic cancer - molecular characterization and therapeutic inhibition
Objectives Pancreatic cancer continues to be the cancer entity with the worst prognosis among all solid tumors associated with a 5-year survival of 5-8%. Combined chemotherapeutic regimes provide only survival benefits for a few months and are not equally suited for all patients with advanced pancreatic cancer. Targeted approaches have largely failed. A marginal clinical benefit was seen for an EGFR inhibitior, erlotinib, in combination with chemotherapy. Using a kinome-wide small-interfering RNA (siRNA)-based loss of function screen, we recently identified the kinase RPS6KA2, also known as p90 ribosomal S6 kinase RSK3, as...
Source: Pancreatology - June 1, 2018 Category: Gastroenterology Authors: Jan Riedel, Nada Milosevic, Jens von Kries, Marc Nazare, Heidi Griesmann, Patrick Michl Tags: 4. Experimental pancreatitis and cell biology II Source Type: research

Low expression of the E3 Ubiquitin Ligase CBL Confers Chemoresistance in Human Pancreatic Cancer and is Targeted by Epidermal Growth Factor Receptor Inhibition.
Conclusions: Low CBL causes chemoresistance in PDAC via stress-induced EGFR activation that can be effectively abrogated by EGFR inhibition. These results suggest that dysregulation of ubiquitination is a key mechanism of EGFR hyperactivation in PDAC and that low CBL may define PDAC tumors likely to respond to erlotinib treatment. PMID: 25348515 [PubMed - as supplied by publisher]
Source: Clinical Cancer Research - October 27, 2014 Category: Cancer & Oncology Authors: Kadera BE, Toste PA, Wu N, Li L, Nguyen AH, Dawson DW, Donahue TR Tags: Clin Cancer Res Source Type: research

Synthetic Lethality Screen Identifies RPS6KA2 as Modifier of Epidermal Growth Factor Receptor Activity in Pancreatic Cancer.
Abstract Pancreatic cancer is characterized by a high degree of resistance to chemotherapy. Epidermal growth factor receptor (EGFR) inhibition using the small-molecule inhibitor erlotinib was shown to provide a small survival benefit in a subgroup of patients. To identify kinases whose inhibition acts synergistically with erlotinib, we employed a kinome-wide small-interfering RNA (siRNA)-based loss-of-function screen in the presence of erlotinib. Of 779 tested kinases, we identified several targets whose inhibition acted synergistically lethal with EGFR inhibition by erlotinib, among them the S6 kinase ribosomal p...
Source: Neoplasia - December 1, 2013 Category: Cancer & Oncology Authors: Milosevic N, Kühnemuth B, Mühlberg L, Ripka S, Griesmann H, Lölkes C, Buchholz M, Aust D, Pilarsky C, Krug S, Gress T, Michl P Tags: Neoplasia Source Type: research