Yap1 Activation Enables Bypass of Oncogenic Kras Addiction in Pancreatic Cancer

Kapoor, Avnish; Yao, Wantong; Ying, Haoqiang; Hua, Sujun; Liewen, Alison; Wang, Qiuyun; Zhong, Yi; Wu, Chang Jiun; Sadanandam, Anguraj; Hu, Baoli; Chang, Qing; Chu, Gerald C.; Al-Khalil, Ramsey; Jiang, Shan; Xia, Hongai; Fletcher-Sananikone, Eliot; Lim, Carol S.; Horwitz, Gillian I.; Viale, Andrea; Pettazzoni, Piergiorgio; Sánchez, Nora; Wang, Huamin; Protopopov, Alexei; Zhang, Jianhua; Heffernan, Timothy P.; Johnson, Randy L.; Chin, Lynda; Wang, Y. Alan; Draetta, Giulio; DePinho, Ronald A.

doi:10.1016/j.cell.2019.10.037

Cited by 101 publications

(136 citation statements)

References 28 publications

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“…on July 7, 2020 http://advances.sciencemag.org/ Downloaded from YAP1 suppression by a YAP1i substantially synergized with a low dose of inRas37 (5 mpk), even slightly regressing the inRas37-sensitive CDXs. These findings suggest that YAP1 overexpression is the adaptive resistance-inducing response of the KRAS MUT -dependent tumor to the KRAS MUT blockade by inRas37, consistent with previous studies suggesting that KRAS MUT depletion by a knockdown causes overexpression of YAP1 to bypass the loss of KRAS MUT signaling in KRAS MUT -dependent CRC and pancreatic cancer cells (42,43). KRAS and YAP1 signaling independently activates transcription factor FOS to regulate tumor survival and epithelial-mesenchymal transition in CRC and NSCLC (43).…”

Section: Discussionsupporting

confidence: 91%

“…However, the combination inRas37 + YAP1i abrogated the overexpression of YAP1. These results suggested that YAP1 overexpression is an adaptive bypass signal transduction counteracting the KRAS MUT -blocking effect of inRas37 in the tumors (42,43). Because YAP1 activates transcription factor FOS to induce tumor survival in the absence of KRAS signaling in colon and lung cancer (43), we examined the FOS activation by monitoring the phosphorylation of FOS.…”

Section: A Combination Of Inras37 With the Yap1 Inhibitor Shows Synermentioning

confidence: 99%

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Direct targeting of oncogenic RAS mutants with a tumor-specific cytosol-penetrating antibody inhibits RAS mutant–driven tumor growth

et al. 2020

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Oncogenic RAS mutant (RASMUT) proteins have been considered undruggable via conventional antibody regimens owing to the intracellular location restricting conventional-antibody accessibility. Here, we report a pan-RAS–targeting IgG antibody, inRas37, which directly targets the intracellularly activated form of various RASMUT subtypes after tumor cell–specific internalization into the cytosol to block the interactions with effector proteins, thereby suppressing the downstream signaling. Systemic administration of inRas37 exerted a potent antitumor activity in a subset of RASMUT tumor xenografts in mice, but little efficacy in RASMUT tumors with concurrent downstream PI3K mutations, which were overcome by combination with a PI3K inhibitor. The YAP1 protein was up-regulated as an adaptive resistance-inducing response to inRas37 in RASMUT-dependent colorectal tumors; accordingly, a combination of inRas37 with a YAP1 inhibitor manifested synergistic antitumor effects in vitro and in vivo. Our study offers a promising pan-RAS–targeting antibody and the corresponding therapeutic strategy against RASMUT tumors.

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Section: Discussionsupporting

confidence: 91%

Section: A Combination Of Inras37 With the Yap1 Inhibitor Shows Synermentioning

confidence: 99%

Direct targeting of oncogenic RAS mutants with a tumor-specific cytosol-penetrating antibody inhibits RAS mutant–driven tumor growth

et al. 2020

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“…Data from this study showed that low AMOT‐p130 coupled with high nuclear YAP1 expression is significantly correlated with high T stage, high TNM stage, and venous invasion, and it is an independent prognostic factor for OS and DFS. Overexpression of YAP1 is significantly related to the malignant potential of gastric carcinoma, hepatocellular carcinoma, ovarian cancer, pancreatic cancer, and lung cancer . In cell line experiments, AMOT‐p130 showed the ability to inhibit YAP1, indicating its potential as a tumor suppressor .…”

Section: Discussionmentioning

confidence: 98%

Low angiomotin‐p130 with concomitant high Yes‐associated protein 1 expression is associated with adverse prognosis of advanced gastric cancer

Hong

Son

Cho

et al. 2017

APMIS

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Lee MS. Low angiomotin-p130 with concomitant high Yes-associated protein 1 expression is associated with adverse prognosis of advanced gastric cancer. APMIS 2017; 125: 996-1006.Angiomotin (AMOT) promotes angiogenesis and plays a role in neovascularization during tumorigenesis. Recently, the AMOT isoform, AMOT-p130, was shown to exert a regulatory effect on Yes-associated protein 1 (YAP1), a major downstream effector of the Hippo pathway. The specific roles of AMOT-p130 and YAP1 in advanced gastric cancer (AGC) are yet to be established. In this study, a total of 166 patients with AGC were enrolled, and AMOT-p130 and YAP1 levels were analyzed by immunohistochemistry using tissue microarrays. Low AMOT-p130 together with high YAP1 expression (n = 30, 18.1%) was associated with high T stage (p = 0.042), high TNM stage (p = 0.025), and venous invasion (p = 0.048). A Kaplan-Meier survival analysis with log-rank test revealed a significant correlation with decreased AMOT-p130 coupled with high nuclear YAP1 expression with shorter overall survival (p = 0.0045) and disease-free survival (p = 0.0028). Furthermore, multivariate analyses showed that the low AMOT-p130/high YAP1 expression profile was an independent prognostic factor for disease-free survival (p = 0.008, HR = 1.874, CI, 1.177-2.986) and overall survival (p = 0.012, HR = 1.903, CI, 1.152-3.143). Our findings collectively demonstrate that low AMOT-p130 combined with high YAP1 expression is correlated with an unfavorable AGC prognosis. RESULTS Clinical and pathological characteristicsAll patients received curative surgical resection (R0). The cohort consisted of both men (n = 118,

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“…Although the underlying mechanisms were not fully elucidated, our current understanding of the physical and pathological roles of YAP1 is supportive of this finding. YAP1 is the main downstream target of the Hippo pathway and acts as a transcriptional coactivator to regulate organ growth, 36,37 tissue homeostasis, 38 and neoplasia, 28,[39][40][41] primarily by interacting with TEAD transcription factors, which subsequently target a series of oncogenes and tumor suppressors to promote cell proliferation, transformation, migration, and invasion. 42,43 YAP1 overexpression has been identified in non-small cell lung cancer, urothelial carcinoma of the bladder, and pancreatic cancer, and is consistently correlated with unfavorable clinical outcomes.…”

Section: Discussionmentioning

confidence: 99%

YAP1 amplification as a prognostic factor of definitive chemoradiotherapy in nonsurgical esophageal squamous cell carcinoma

Dai

Shao

Tong³

et al. 2019

Cancer Medicine

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Background Definitive chemoradiation therapy (dCRT) is the standard treatment for patients with nonsurgical esophageal squamous cell carcinoma (ESCC), yet patients have demonstrated great variations in their responses to dCRT and inevitably progressed following treatment. Methods To identify prognostic biomarkers, we performed targeted next‐generation sequencing of 416 cancer‐related genes on primary tumors from 47 nonsurgical ESCC patients prior to dCRT treatment. The association between genetic alterations and patients' local recurrence‐free survival (LRFS), progression‐free survival (PFS), and overall survival (OS) was analyzed. Results TP53 (78% of patients), NOTCH1 (32%), ARID1A (13%), FAT1 (13%), and CDKN2A (13%) were commonly mutated in ESCC patients, while gene amplifications frequently occurred in MCL1 (36%), FGF19 (34%), MYC (32%), CCND1 (27%), ZNF217 (15%), CDKN2A (13%), and YAP1 (11%). Univariate and multivariate analyses of clinical factors and genetic alterations indicated that sex is an independent prognostic factor, with males tending to have better LRFS (hazard ratio [HR], 0.25; 95%CI, 0.08‐0.77, P = .015) and progression‐free survival (PFS) (HR, 0.35; 95%CI, 0.13‐0.93, P = .030) following dCRT. Meanwhile, YAP1 amplification (n = 7) was an adverse prognostic factor, and patients with this alteration demonstrated a tendency toward worse outcomes with shorter LRFS (HR, 4.06; 95%CI, 1.26‐13.14, P = .019) and OS (HR, 2.78; 95%CI, 0.95‐8.17, P = .062). In a subgroup analysis, while sex and M‐stage were controlled, a much stronger negative effect of YAP1 amplification vs wild‐type in LRFS was observed (log‐rank P = .0067). Conclusion The results suggested that YAP1 amplification is a potentially useful biomarker for predicting treatment outcomes and identifying patients with a high risk of relapse who should be closely monitored.

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Yap1 Activation Enables Bypass of Oncogenic Kras Addiction in Pancreatic Cancer

Cited by 101 publications

References 28 publications

Direct targeting of oncogenic RAS mutants with a tumor-specific cytosol-penetrating antibody inhibits RAS mutant–driven tumor growth

Direct targeting of oncogenic RAS mutants with a tumor-specific cytosol-penetrating antibody inhibits RAS mutant–driven tumor growth

Low angiomotin‐p130 with concomitant high Yes‐associated protein 1 expression is associated with adverse prognosis of advanced gastric cancer

YAP1 amplification as a prognostic factor of definitive chemoradiotherapy in nonsurgical esophageal squamous cell carcinoma

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