Yap1 Activation Enables Bypass of Oncogenic Kras Addiction in Pancreatic Cancer

Abstract

SUMMARY Activating mutations in KRAS are among the most frequent events in diverse human carcinomas and are particularly prominent in human pancreatic ductal adenocarcinoma (PDAC). An inducible KrasG12D-driven mouse model of PDAC has established a critical role for sustained KrasG12D expression in tumor maintenance, providing a model to determine the potential for, and the underlying mechanisms of, KrasG12D–independent PDAC recurrence. Here we show that some tumors undergo spontaneous relapse and are devoid of KrasG12D expression and downstream canonical MAPK signaling and instead acquire amplification and overexpression of the transcriptional co-activator Yap1. Functional studies established the role of Yap1 and the transcriptional factor Tead2 in driving KrasG12D–independent tumor maintenance. The Yap1/Tead2 complex acts cooperatively with E2F transcription factors to activate a cell cycle and DNA replication program. Our studies, along with corroborating evidence from human PDAC models, portend a novel mechanism of escape from oncogenic Kras addiction in PDAC.

Genetics and biology of pancreatic ductal adenocarcinoma

“…In this model, oncogenic Kras extinction permanently eliminates most tumors; however, a subset of tumors can bypass Kras dependency and undergoes spontaneous recurrence (Kapoor et al 2014). Multidimensional genomic, transcriptomic, and proteomic profiling has revealed several distinct mechanisms, including, most prominently, amplification of the Yap1 oncogene of the Hippo pathway (Kapoor et al 2014).…”

“…In this model, oncogenic Kras extinction permanently eliminates most tumors; however, a subset of tumors can bypass Kras dependency and undergoes spontaneous recurrence (Kapoor et al 2014). Multidimensional genomic, transcriptomic, and proteomic profiling has revealed several distinct mechanisms, including, most prominently, amplification of the Yap1 oncogene of the Hippo pathway (Kapoor et al 2014). Interestingly, YAP1 was also identified in multiple genetic screens as one of the top hits that confer resistance to KRAS suppression or targeted cancer therapy with RAF and MEK inhibitors (Shao et al 2014;Lin et al 2015), further corroborating the role of the YAP1 pathway in driving resistance to targeted therapy.…”

FGF8 promotes cell proliferation and resistance to EGFR inhibitors via upregulation of EGFR in human hepatocellular carcinoma cells

“…YAP1 is a transcriptional coactivator in the Hippo signaling pathway (15). Increased YAP1 expression or activity can promote the growth of tumor cells, including human HCC (14,16).…”

“…It was reported that β-catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis (14). Enforced YAP1 expression can enable tumor maintenance upon Kras G12D extinction in a human pancreatic ductal adenocarcinoma model (15). Moreover, YAP1 amplification has been described as an essential oncogene in various types of human cancers, including human HCC (16).…”

Engineering solutions for cancer

“…Other areas where there is obvious potential for engineering input include: novel biosensors and pointof-care diagnostics for early detection of disease via the capture and detection of circulating biomarkers (liquid biopsies) [24][25][26][27]; the use of smart wearable or implantable electrochemical sensors to characterise tumour response to chemotherapy in situ or to monitor disease progression and/or signs of relapse [28,29]; artificial intelligence (AI), such as machine learning to help physicians make better diagnoses and guide treatment decisions while minimising costs [30]; metabolic and proteomic profiling of body fluids for the identification of tumoural areas in situ [31][32][33]; and disease-detecting or disease-fighting nanotechnologies (e.g. DNA nanobots [34], quantum dots [35]) for reporting disease status and selectively delivering drugs to tumour cells whilst minimising systemic side effects [36].…”