Grant Trevor J, Mehta Anita K, Gupta Anamika, Sharif Ahmad A D, Arora Kshitij S, Deshpande Vikram, Ting David T, Bardeesy Nabeel, Ganem Neil J, Hergovich Alexander, Singh Anurag
Department of Pharmacology and Experimental Therapeutics, Center for Cancer Research, Boston University Graduate School of Medicine, Boston, MA, USA.
University College London, Cancer Institute, London, United Kingdom.
Oncotarget. 2017 Sep 11;8(45):78556-78572. doi: 10.18632/oncotarget.20833. eCollection 2017 Oct 3.
Pancreatic ductal adenocarcinomas (PDACs) are highly aggressive malignancies, associated with poor clinical prognosis and limited therapeutic options. Oncogenic 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 gene is located on chromosome 12p11-12p12, a region amplified in 5-10% of primary PDACs. Within this amplicon, we identified co-amplification of with the gene in a subset of primary human PDACs and PDAC cell lines. Therefore, we determined whether PDAC cell lines are dependent on expression for proliferation and viability. encodes a serine/threonine kinase, which shares homology with Hippo pathway kinases LATS1/2. We show that 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 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.
胰腺导管腺癌（PDAC）是极具侵袭性的恶性肿瘤，临床预后较差且治疗选择有限。超过90%的PDAC中存在致癌突变，在肿瘤进展中起核心作用。PDAC的全基因组表达谱揭示了3 - 4种主要分子亚型，具有不同的表型特征和药物敏感性，包括致癌KRAS通路依赖性的差异。异常分化的内分泌外分泌（ADEX）亚型的PDAC细胞系在生存方面强烈依赖KRAS。该基因位于12号染色体p11 - 12p12区域，在5% - 10%的原发性PDAC中发生扩增。在这个扩增子内，我们在一部分原发性人类PDAC和PDAC细胞系中鉴定出该基因与另一个基因的共扩增。因此，我们确定PDAC细胞系是否依赖该基因的表达来进行增殖和维持生存能力。该基因编码一种丝氨酸/苏氨酸激酶，与Hippo通路激酶LATS1/2具有同源性。我们发现，在一部分表现出ADEX亚型特征（包括突变KRAS过表达）的原发性PDAC和PDAC细胞系中，该基因的表达升高。RNA干扰介导的对一部分ADEX亚型细胞系中该基因的缺失抑制了细胞增殖并诱导了细胞凋亡。伴随着这些效应，该基因的缺失导致LATS2激酶和细胞周期调节因子p21的表达增加。LATS2的缺失部分挽救了该基因缺失的细胞抑制和细胞毒性作用。最后，该基因的高mRNA表达与PDAC患者的总生存期降低相关。总体而言，我们的研究结果表明该基因是分子定义的一部分PDAC中的一个潜在可靶向的弱点。
