Anti-STK38L monoclonal antibody, clone 5E9

The metazoan Hippo pathway is an essential tumour suppressor signalling cascade that ensures normal tissue growth by co-ordinating cell proliferation, cell death and cell differentiation. Over the past years, various genetic and biochemical studies in Drosophila and mammals have defined a conserved core Hippo signalling module, composed of members of the Ste20-like kinase, the MOB co-activator and the AGC kinase families. In Drosophila, stimulated Hippo kinase phosphorylates and thereby activates the Mats/Warts complex, which consequently phosphorylates and inactivates the transcriptional co-activator Yorkie. In mammals, the counterparts of the Hippo/Mats/Warts/Yorkie cascade, namely MST1/2, MOB1A/B, LATS1/2 and YAP/TAZ, function in a similar fashion. These canonical Hippo pathways are so highly conserved that human MST2, hMOB1A and LATS1 can compensate for the loss of Hippo, Mats and Warts in flies. However, recent reports have shown that Hippo signalling is more diverse and complex, in particular in mammals. In this review, we summarize our current understanding of mammalian LATS1/2 kinases together with their closest relatives, the NDR1/2 kinases. The regulation of the LATS/NDR family of kinases will be discussed, followed by a summary of all currently known LATS/NDR substrates. Last, but not least, the biological roles of LATS/NDR kinases will be reviewed with specific emphasis on recent discoveries of canonical and non-canonical LATS/NDR functions in the extended Hippo pathway.

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.