PI3K inhibition in combination with other agents has not been studied in the context of PIK3CA wild-type, KRAS mutant cancer. In a screen of phospho-kinases, PI3K inhibition of KRAS mutant colorectal cancer cells activated the MAPK pathway. Combination PI3K/MEK inhibition with NVP-BKM120 and PD-0325901 induced tumor regression in a mouse model of PIK3CA wild-type, KRAS mutant colorectal cancer, which was mediated by inhibition of mTORC1, inhibition of MCL-1, and activation of BIM. These findings implicate mitochondrial-dependent apoptotic mechanisms as determinants for the efficacy of PI3K/MEK inhibition in the treatment of PIK3CA wild-type, KRAS mutant cancer.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118771 | PMC |
http://dx.doi.org/10.1016/j.canlet.2014.02.018 | DOI Listing |
Cancer Res
January 2025
University of Cambridge, Cambridge, United Kingdom.
Pancreatic ductal adenocarcinoma (PDAC) contains an extensive stroma that modulates response to therapy, contributing to the dismal prognosis associated with this cancer. Evidence suggests that PDAC stromal composition is shaped by mutations within malignant cells, but most previous work has focused on pre-clinical models driven by KrasG12D and mutant Trp53. Elucidation of the contribution of additional known oncogenic drivers, including KrasG12V mutation and Smad4 loss, is needed to increase understanding of malignant cell-stroma crosstalk in PDAC.
View Article and Find Full Text PDFMol Oncol
January 2025
Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Italy.
Specific reactive oxygen species activate the GTPase Kirsten rat sarcoma virus (KRAS) by reacting with cysteine 118 (C118), leading to an electron transfer between C118 and nucleoside guanosine diphosphate (GDP), which causes the release of GDP. Here, we have mimicked permanent oxidation of human KRAS at C118 by replacing C118 with aspartic acid (C118D) in KRAS to show that oncogenic mutant KRAS is selectively inhibited via oxidation at C118, both in vitro and in vivo. Moreover, the combined treatment of hydrogen-peroxide-producing pro-oxidant paraquat and nitric-oxide-producing inhibitor N(ω)-nitro-l-arginine methyl ester selectively inhibits human mutant KRAS activity by inducing oxidization at C118.
View Article and Find Full Text PDFMol Cancer Ther
January 2025
Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
Mutations in the KRAS oncogene can mediate resistance to radiation. KRAS mutation (mut) driven tumors have been reported to express cancer stem cell (CSC)-like features and may harbor metabolic liabilities through which CSC-associated radioresistance can be overcome. We established a radiation/drug screening approach that relies on the growth of 3D spheres under anchorage-independent and lipid-limiting culture conditions, which promote stemness and lipogenesis.
View Article and Find Full Text PDFAnn Pancreat Cancer
June 2024
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Background: Pancreatic ductal adenocarcinoma (PDAC) is predicted to be the second leading cause of cancer-related death by 2030. This is driven by a high case-fatality rate with most patients even with radiologically localized PDAC at diagnosis ultimately relapsing with metastatic disease. mutations present in 90% to 95% of PDAC drive these poor statistics through its role in driving cellular growth, inhibition of apoptosis, and immunosuppression.
View Article and Find Full Text PDFJ Transl Med
January 2025
Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Background: KRAS-G12C inhibitors mark a notable advancement in targeted cancer therapies, yet identifying predictive biomarkers for treatment efficacy and resistance remains essential for optimizing clinical outcomes.
Methods: This systematic meta-analysis synthesized studies available through September 2024 across PubMed, Cochrane Library, SpringerLink, and Embase. Using CRISPR/Cas9 technology, this study generated cells with KEAP1 and STK11 knockouts, and utilized lentiviral vectors to overexpress PD-L1.
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!