SUMMARY Induction of compensatory mechanisms and ERK reactivation has limited the effectiveness of Raf and MEK inhibitors in RAS-mutant cancers. We determined that direct pharmacologic inhibition of ERK suppressed the growth of a subset of KRAS-mutant pancreatic cancer cell lines and that concurrent PI3K inhibition caused synergistic cell death. Additional combinations that enhanced ERK inhibitor action were also identified. Unexpectedly, long-term treatment of sensitive cell lines caused senescence, mediated in part by MYC degradation and p16 reactivation. Enhanced basal PI3K-AKT-mTOR signaling was associated with de novo resistance to ERK inhibitor, as were other protein kinases identified by kinome-wide siRNA screening and a genetic gain-of-function screen. Our findings reveal distinct consequences of inhibiting this kinase cascade at the level of ERK.
Pancreatic cancer is characterized by a desmoplastic reaction that creates a dense fibroinflammatory microenvironment, promoting hypoxia and limiting cancer drug delivery due to decreased blood perfusion. Here we describe a novel tumor-stroma interaction that may help explain the prevalence of desmoplasia in this cancer. Specifically, we found that activation of HIF-1α by tumor hypoxia strongly activates secretion of the sonic hedgehog ligand SHH by cancer cells which in turn causes stromal fibroblasts to increase fibrous tissue deposition. In support of this finding, elevated levels of HIF-1α and SHH in pancreatic tumors were determined to be markers of decreased patient survival. Repeated cycles of hypoxia and desmoplasia amplified each other in a feed forward loop that made tumors more aggressive and resistant to therapy. This loop could be blocked by HIF-1α inhibition, which was sufficient to block SHH production and HH signaling. Taken together, our findings suggest that increased HIF-1α produced by hypoxic tumors triggers the desmoplasic reaction in pancreatic cancer, which is then amplified by a feed forward loop involving cycles of decreased blood flow and increased hypoxia. our findings strengthen the rationale for testing HIF inhibitors may therefore represent a novel therapeutic option for pancreatic cancer.
The Cub and Sushi Multiple Domains-1 (CSMD1) is a tumor suppressor gene on 8p23.2, where allelic loss is both frequent and associated with poor prognosis in head and neck squamous cell carcinoma (HNSCC). To understand the extent of CSMD1 aberrations in vivo, we characterized 184 primary tumors from the head and neck, lung, breast and skin for gene copy number and analyzed expression in our HNSCCs and lung squamous cell carcinomas (SCCs).We detected loss of CSMD1 in a large proportion of HNSCCs (50%), lung (46%) and breast cancers (55%), and to a lesser extent in cutaneous SCCs (29%) and basal cell carcinomas (BCCs, 17%) using array-based comparative genomic hybridization (aCGH). Studying the region more closely with quantitative real-time PCR (qPCR), the loss of CSMD1 increased to 80% in HNSCCs and 93% in lung SCCs. CSMD1 expression was decreased in tumors compared to adjacent benign tissue (65%, 13/20) and was likely due to gene loss in 45% of cases (9/20). We also identified truncated transcripts lacking exons due to DNA copy number loss (30%, 5/17) or aberrant splicing (24%, 4/17).We show loss of CSMD1 in primary HNSCC tissues, and document for the first time that CSMD1 is lost in breast, lung and cutaneous SCCs. We also show that deletions of CSMD1 and aberrant splicing contribute to altered CSMD1 function in vivo.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.