STK38L kinase ablation promotes loss of cell viability in a subset of KRAS-dependent pancreatic cancer cell lines
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Trevor J. Grant1, Anita K. Mehta1, Anamika Gupta1, Ahmad A.D. Sharif2, Kshitij S. Arora3, Vikram Deshpande3, David T. Ting3, Nabeel Bardeesy3, Neil J. Ganem1, Alexander Hergovich2 and Anurag Singh1
1Department of Pharmacology and Experimental Therapeutics, Center for Cancer Research, Boston University Graduate School of Medicine, Boston, MA, USA
2University College London, Cancer Institute, London, United Kingdom
3Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, USA
Anurag Singh, email: email@example.com
Keywords: KRAS, oncogene dependency, Hippo pathway, pancreatic cancer, kinase
Received: July 12, 2017 Accepted: August 27, 2017 Published: September 11, 2017
Pancreatic ductal adenocarcinomas (PDACs) are highly aggressive malignancies, associated with poor clinical prognosis and limited therapeutic options. Oncogenic KRAS mutations are found in over 90% of PDACs, playing a central role in tumor progression. Global gene expression profiling of PDAC reveals 3-4 major molecular subtypes with distinct phenotypic traits and pharmacological vulnerabilities, including variations in oncogenic KRAS pathway dependencies. PDAC cell lines of the aberrantly differentiated endocrine exocrine (ADEX) subtype are robustly KRAS-dependent for survival. The KRAS gene is located on chromosome 12p11-12p12, a region amplified in 5-10% of primary PDACs. Within this amplicon, we identified co-amplification of KRAS with the STK38L gene in a subset of primary human PDACs and PDAC cell lines. Therefore, we determined whether PDAC cell lines are dependent on STK38L expression for proliferation and viability. STK38L encodes a serine/threonine kinase, which shares homology with Hippo pathway kinases LATS1/2. We show that STK38L expression is elevated in a subset of primary PDACs and PDAC cell lines displaying ADEX subtype characteristics, including overexpression of mutant KRAS. RNAi-mediated depletion of STK38L in a subset of ADEX subtype cell lines inhibits cellular proliferation and induces apoptosis. Concomitant with these effects, STK38L depletion causes increased expression of the LATS2 kinase and the cell cycle regulator p21. LATS2 depletion partially rescues the cytostatic and cytotoxic effects of STK38L depletion. Lastly, high STK38L mRNA expression is associated with decreased overall patient survival in PDACs. Collectively, our findings implicate STK38L as a candidate targetable vulnerability in a subset of molecularly-defined PDACs.
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