An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer
نویسندگان
چکیده
KRAS mutated tumours represent a large fraction of human cancers, but the vast majority remains refractory to current clinical therapies. Thus, a deeper understanding of the molecular mechanisms triggered by KRAS oncogene may yield alternative therapeutic strategies. Here we report the identification of a common transcriptional signature across mutant KRAS cancers of distinct tissue origin that includes the transcription factor FOSL1. High FOSL1 expression identifies mutant KRAS lung and pancreatic cancer patients with the worst survival outcome. Furthermore, FOSL1 genetic inhibition is detrimental to both KRAS-driven tumour types. Mechanistically, FOSL1 links the KRAS oncogene to components of the mitotic machinery, a pathway previously postulated to function orthogonally to oncogenic KRAS. FOSL1 targets include AURKA, whose inhibition impairs viability of mutant KRAS cells. Lastly, combination of AURKA and MEK inhibitors induces a deleterious effect on mutant KRAS cells. Our findings unveil KRAS downstream effectors that provide opportunities to treat KRAS-driven cancers.
منابع مشابه
Quo vadis, Kras?
Somatic mutations in the Ras oncogene family (KRas, HRas, and NRas) occur in up to 30% of human cancers. Due to this high mutation frequency and the recent observation that survival of KrasG12D-driven cancer cells depends on the continuous expression of the oncogene in vivo [1, 2], mutant Kras is an excellent therapeutic target. However, efforts to develop drugs, which directly target mutant Kr...
متن کاملmiRNA-96 suppresses KRAS and functions as a tumor suppressor gene in pancreatic cancer.
Therapeutic applications of microRNA (miRNA) in KRAS-driven pancreatic cancers might be valuable, but few studies have explored this area. Here, we report that miR-96 directly targets the KRAS oncogene and functions as a tumor-suppressing miRNA in pancreatic cancer cells. Ectopic expression of miR-96 through a synthetic miRNA precursor inhibited KRAS, dampened Akt signaling, and triggered apopt...
متن کاملSelective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer.
Oncogenic Kras activates a plethora of signaling pathways, but our understanding of critical Ras effectors is still very limited. We show that cell-autonomous phosphoinositide 3-kinase (PI3K) and 3-phosphoinositide-dependent protein kinase 1 (PDK1), but not Craf, are key effectors of oncogenic Kras in the pancreas, mediating cell plasticity, acinar-to-ductal metaplasia (ADM), and pancreatic duc...
متن کاملمطالعه بررسی بیان ژن های KRAS و NRAS افراد مبتلا به سرطان ریه نسبت به گروه سالم
Background: Lung cancer is one of the most common cancers around the world, and a major cause of death. The KRAS and NRAS genes could cause malfunction in signal transduction and cell cycle regulation. Materials and Methods: In this study, the expression level of KRAS and NRAS biomarkers among 50 lung cancer patients in comparison with 50 normal individuals was investigated. Total RNA from blo...
متن کاملTwo is better than one: combining IGF1R and MEK blockade as a promising novel treatment strategy against KRAS-mutant lung cancer.
A small-molecule inhibitor screen on a panel of human lung cancer cell lines has uncovered an unexpected sensitivity of cells expressing oncogenic KRAS toward insulin-like growth factor 1 receptor (IGF1R) inhibition. Combining IGF1R and MAP-ERK kinase blockade led to significant effects on viability in human non-small cell lung cancer (NSCLC) cell lines and in 2 mouse models of oncogenic KRAS-d...
متن کامل