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• W1994448486 abstract "It is of great therapeutic importance to understand why tumors relapse after the failure of therapies targeting oncogenes to which cancer cells are addicted. In this issue, Kapoor et al. and Shao et al. identify the transcriptional coactivator YAP1 as a central driver of compensation for the loss of K-Ras signaling in K-Ras-dependent cancers. It is of great therapeutic importance to understand why tumors relapse after the failure of therapies targeting oncogenes to which cancer cells are addicted. In this issue, Kapoor et al. and Shao et al. identify the transcriptional coactivator YAP1 as a central driver of compensation for the loss of K-Ras signaling in K-Ras-dependent cancers. Targeted therapies of oncogene-addicted tumors have led to significant clinical responses in various malignancies, including Erb2 overexpressing breast cancer, chronic myelogeneous leukemia harboring the BCR-ABL translocation, non-small cell lung cancer with a subset of EGFR mutations, or BRAF mutant melanoma (Torti and Trusolino, 2011Torti D. Trusolino L. EMBO. Mol. Med. 2011; 3: 623-636Crossref PubMed Scopus (184) Google Scholar). Unfortunately, in almost all cases, resistance development and tumor relapse occur. Somatic mutations in KRAS belong to the most common activating lesions found in human cancer, including pancreas, lung, and colon cancer (Karnoub and Weinberg, 2008Karnoub A.E. Weinberg R.A. Nat. Rev. Mol. Cell Biol. 2008; 9: 517-531Crossref PubMed Scopus (1124) Google Scholar). Thus, K-Ras inhibition bears great clinical impact, yet identification of potential resistance mechanisms is of enormous therapeutic relevance. In this issue of Cell, two studies provide compelling evidence that Yes-associated protein 1 (YAP1) can substitute for loss of KRAS in human and murine cancers. Pancreatic ductal adenocarcinoma (PDAC) represents one of the best examples of a tumor with a very high dependence on oncogenic KRAS, and the DePinho group had recently demonstrated that sustained K-Ras activation is essential for maintenance of PDAC (Ying et al., 2012Ying H. Kimmelman A.C. Lyssiotis C.A. Hua S. Chu G.C. Fletcher-Sananikone E. Locasale J.W. Son J. Zhang H. Coloff J.L. et al.Cell. 2012; 149: 656-670Abstract Full Text Full Text PDF PubMed Scopus (1281) Google Scholar). In a very elegant report, the same group now employs a genetic mouse model to examine the long-term effects upon shutdown of oncogenic K-Ras in established pancreatic cancer (Kapoor et al., 2014Kapoor A. Yao W. Ying H. Hua S. Liewen A. Wang Q. Zhong Y. Wu C.-J. Sadanandam A. Hu B. et al.Cell. 2014; 158 (this issue): 185-197Google Scholar). As expected, all tumors initially regress within 3 weeks after K-rasG12D extinction; however, more than two-thirds of tumors begin to relapse after about 2 months. These are confirmed to be bona fide tumor relapses yet display a more aggressive phenotype with a higher number of distant metastases. Although MEK/ERK signaling is activated in about half of the relapsed tumors due to re-expression of the Kras transgene, the other half of tumors is characterized by amplification of chromosome 9qA1 encompassing genes coding for the transcriptional coactivator Yap1 and the antiapoptotic genes Birc2 and Birc3. Of these, only knockdown of Yap1 affects pancreatic cancer cell growth, and enforced Yap1 expression enables pancreatic tumor maintenance even in the absence of oncogenic K-Ras in vivo. Although Yap1 is known to interact with Smad1, p73, Runx2, and TEAD transcription factors (Zhao et al., 2011Zhao B. Tumaneng K. Guan K.L. Nat. Cell Biol. 2011; 13: 877-883Crossref PubMed Scopus (861) Google Scholar), the authors demonstrate in the pancreatic cancer model that Yap1 complexes specifically with Tead2. This complex then cooperates with E2F transcription factors to activate genes controlling cell cycle and DNA replication. Accordingly, dominant-negative E2F1 suppresses proliferation of YAP1-expressing cancer cells, underscoring the importance of E2F1 activity for YAP1/Tead2-mediated bypass of tumor regression in the absence of oncogenic K-Ras. Importantly, the authors highlight the clinical importance of their findings. Most YAP1-expressing relapse tumors express gene signatures comparable to the human quasimesenchymal subtype of PDAC, which in contrast to the other two PDAC subtypes (classical and exocrine-like), is known to express lower levels of KRAS and to be less KRAS dependent. Indeed, YAP1 proves to be essential for growth of tumor cell lines derived from quasimesenchymal tumors. Based on the results of a genome-scale screen Hahn, Jacks, and colleagues describe that YAP1 can specifically compensate the shRNA-mediated loss of K-Ras function in KRAS mutant colon and pancreatic cancer cell lines (Shao et al., 2014Shao D.D. Xue W. Krall E.B. Bhutkar A. Piccioni F. Wang X. Schinzel A.C. Sood S. Rosenbluh J. Kim J.W. et al.Cell. 2014; 158 (this issue): 171-184Google Scholar). In contrast to the study by DePinho here, YAP1 functions independently of TEAD. Instead, YAP1 controls the AP-1 family transcription factor FOS and epithelial-mesenchymal transition (EMT). YAP1 specifically interacts with FOS, but not with other AP-1 family members such as Jun to coordinately regulate downstream targets involved in EMT, including vimentin and slug. Using an oncogenic K-Ras-dependent lung cancer model, the authors confirm rapid tumor regression upon loss of K-Ras signaling as well as K-Ras-independent tumor relapse shortly after. Cell lines obtained from these K-Ras-silenced tumors show a YAP1 signature as well as altered expression of various EMT markers. When K-Ras and YAP1 are both silenced in the lung tumor model in vivo, tumor relapse is delayed; however, in these tumors, YAP1 is not silenced anymore. The Hippo pathway controls YAP1 activity via activation of the kinases MST1 and MST2 as well as LATS1 and LATS2. This pathway is involved in embryonic development, tissue homeostasis, and tumorigenesis (Zhao et al., 2011Zhao B. Tumaneng K. Guan K.L. Nat. Cell Biol. 2011; 13: 877-883Crossref PubMed Scopus (861) Google Scholar). YAP itself acts as an oncogene both in vitro and in vivo and is frequently amplified in a wide range of cancers, including breast and liver, controlling cell proliferation, EMT, invasion, and metastasis. The two studies published here add a new central function for YAP1: they place YAP1 as an essential bypass in K-Ras-dependent tumors once K-Ras signaling is silenced (Figure 1). Using independent in vivo and ex vivo approaches in different cancer entities, both studies identify YAP1 as the primary substitute for K-Ras. Intriguingly, the responsible downstream effector mechanisms ultimately leading to tumor relapse differ in distinct tumor entities despite the fact that YAP1 is involved in both cases. Presumably this is due to the context-dependent versatility of YAP1 to interact with various transcription factors. Considering the high frequency of KRAS mutant cancers as well as the fact that K-Ras is slowly losing its “undruggable” status (Ostrem et al., 2013Ostrem J.M. Peters U. Sos M.L. Wells J.A. Shokat K.M. Nature. 2013; 503: 548-551Crossref PubMed Scopus (1272) Google Scholar), these two studies mark a great step forward in the efforts to identify potential resistance mechanisms. Moreover, recently developed YAP1 inhibitors targeting YAP-TEAD complexes may become of increasing value (Stanger, 2012Stanger B.Z. Genes Dev. 2012; 26: 1263-1267Crossref PubMed Scopus (44) Google Scholar). So far, this may be limited to treatment of liver, pancreatic, and gastric cancer when YAP-TEAD complexes are involved. Importantly, however, such compounds may function even in the presence of oncogenic K-Ras, as loss of YAP1 protects from PDAC development also when K-Ras signaling is intact (Zhang et al., 2014Zhang W. Nandakumar N. Shi Y. Manzano M. Smith A. Graham G. Gupta S. Vietsch E.E. Laughlin S.Z. Wadhwa M. et al.Sci. Signal. 2014; 7: ra42Crossref PubMed Scopus (265) Google Scholar). In PDAC and K-Ras-silenced colon cancer cells, YAP1 seems to be activated independently of the Hippo pathway. This raises the question of what the responsible K-Ras-controlled and -independent pathways are that trigger YAP1 activation under various conditions. In K-Ras-silenced PDAC, chromosomal amplifications cause increased YAP1 copy numbers (Kapoor et al., 2014Kapoor A. Yao W. Ying H. Hua S. Liewen A. Wang Q. Zhong Y. Wu C.-J. Sadanandam A. Hu B. et al.Cell. 2014; 158 (this issue): 185-197Google Scholar). However, in lung and colorectal cancer, this does not seem to be the case. It is possible that there are common context-specific YAP activators that may also explain the interaction with distinct transcription factors, which may ultimately allow more feasible therapeutic targeting of this central coactivator. These new studies undoubtedly provide a compelling rationale to target YAP1. Work in the lab of F.R.G. is supported by the Deutsche Forschungsgemeinschaft (GR 1916/3-1), the European Research Council (ERC 281967), and the LOEWE Center for Cell and Gene Therapy Frankfurt funded by the Hessian Ministry of Higher Education, Research and the Arts; III L 4-518/17.004. KRAS and YAP1 Converge to Regulate EMT and Tumor SurvivalShao et al.CellJune 19, 2014In BriefThe transcriptional regulation of the epithelial-mesenchymal transition by the transcriptional coactivator YAP1 is a critical feature of cancer cell dependence on oncogenic KRAS. Full-Text PDF Open ArchiveYap1 Activation Enables Bypass of Oncogenic Kras Addiction in Pancreatic CancerKapoor et al.CellJune 19, 2014In BriefIn a mouse model of pancreatic cancer, amplification of Yap1 allows tumor cells to escape addiction to oncogenic Kras Full-Text PDF Open Archive" @default.
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• W1994448486 title "YAP1 Takes Over when Oncogenic K-Ras Slumbers" @default.
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