Oncogenic KRAS signaling and YAP1/β-catenin: Similar cell cycle control in tumor initiation (original) (raw)
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KRAS Oncogenic Signaling Extends beyond Cancer Cells to Orchestrate the Microenvironment
Cancer research, 2018
KRAS is one of the most frequently mutated oncogenes in cancer, being a potent initiator of tumorigenesis, a strong inductor of malignancy, and a predictive biomarker of response to therapy. Despite the large investment to understand the effects of KRAS activation in cancer cells, pharmacologic targeting of KRAS or its downstream effectors has not yet been successful at the clinical level. Recent studies are now describing new mechanisms of KRAS-induced tumorigenesis by analyzing its effects on the components of the tumor microenvironment. These studies revealed that the activation of KRAS on cancer cells extends to the surrounding microenvironment, affecting the properties and functions of its constituents. Herein, we discuss the most emergent perspectives on the relationship between KRAS-mutant cancer cells and their microenvironment components..
Cancer Research, 2012
Early biomarkers and effective therapeutic strategies are desperately needed to treat pancreatic ductal adenocarcinoma (PDAC), which has a dismal 5-year patient survival rate. Here, we report that the novel tyrosine kinase PEAK1 is upregulated in human malignancies, including human PDACs and pancreatic intraepithelial neoplasia (PanIN). Oncogenic KRas induced a PEAK1-dependent kinase amplification loop between Src, PEAK1, and ErbB2 to drive PDAC tumor growth and metastasis in vivo. Surprisingly, blockade of ErbB2 expression increased Src-dependent PEAK1 expression, PEAK1-dependent Src activation, and tumor growth in vivo, suggesting a mechanism for the observed resistance of patients with PDACs to therapeutic intervention. Importantly, PEAK1 inactivation sensitized PDAC cells to trastuzumab and gemcitabine therapy. Our findings, therefore, suggest that PEAK1 is a novel biomarker, critical signaling hub, and new therapeutic target in PDACs. Cancer Res; 72(10); 2554-64. Ó2012 AACR. Figure 2. KRas induces Src-dependent PEAK1 expression in PDAC and other human malignancies. A, qPCR analyses of PEAK1 in oncogenic KRas-containing PDAC tissues collected from patients BK-13 and BK-14 relative to normal pancreas tissue from the same patients. Error bars, SD over 3 analyses. B, hematoxylin and eosin (H&E) staining and PEAK1 immunohistochemistry of tissues from patients BK-13 and BK-14. C, heatmap of fold change in PEAK1 expression in tumor samples with and without oncogenic Ras mutations. Data are publicly available on Oncomine, and citations are included in Supplementary Data. D, Western blot (WB) analysis for PEAK1 and KRas in HPNE (11, or PDAC cell lines (FG and PANC1). E, quantification of protein (left) and mRNA (right) levels of PEAK1 following administration of indicated pathway inhibitors in HPNE-KRas and PANC1 cells, relative to dimethyl sulfoxide (DMSO) vehicle control.
From basic researches to new achievements in therapeutic strategies of KRAS-driven cancers
Cancer Biology & Medicine
Among the numerous oncogenes involved in human cancers, KRAS represents the most studied and best characterized cancer-related genes. Several therapeutic strategies targeting oncogenic KRAS (KRASonc) signaling pathways have been suggested, including the inhibition of synthetic lethal interactions, direct inhibition of KRASonc itself, blockade of downstream KRASonc effectors, prevention of post-translational KRASonc modifications, inhibition of the induced stem cell-like program, targeting of metabolic peculiarities, stimulation of the immune system, inhibition of inflammation, blockade of upstream signaling pathways, targeted RNA replacement, and oncogene-induced senescence. Despite intensive and continuous efforts, KRASonc remains an elusive target for cancer therapy. To highlight the progress to date, this review covers a collection of studies on therapeutic strategies for KRAS published from 1995 to date. An overview of the path of progress from earlier to more recent insights hi...
2011
Oncogenic KRAS is found in >25% of lung adenocarcinomas, the major histologic subtype of non-small cell lung cancer (NSCLC), and is an important target for drug development. To this end, we generated four NSCLC lines with stable knockdown selective for oncogenic KRAS. As expected, stable knockdown of oncogenic KRAS led to inhibition of in vitro and in vivo tumor growth in the KRAS mutant NSCLC cells, but not in NSCLC cells that have wild-type KRAS (but mutant NRAS). Surprisingly, we did not see large-scale induction of cell death and the growth inhibitory effect was not complete. To further understand the ability of NSCLCs to grow despite selective removal of mutant KRAS expression, we performed microarray expression profiling of NSCLC cell lines with or without mutant KRAS knockdown and isogenic human bronchial epithelial cell lines (HBECs) with and without oncogenic KRAS. We found that while the MAPK pathway is significantly down-regulated after mutant KRAS knockdown, these NSCLCs showed increased levels of phospho-STAT3 and phospho-EGFR, and variable changes in phospho-Akt. In addition, mutant KRAS knockdown sensitized the NSCLCs to p38 and EGFR inhibitors. Our
to Activation of PI3 Kinase in KRAS-Mutant Lung Cancer
2013
Using a panel of non–small cell lung cancer (NSCLC) lines, we show here that MAP-ERK kinase (MEK) and RAF inhibitors are selectively toxic for the KRAS-mutant genotype, whereas phosphoinositide 3-kinase (PI3K), AKT, and mTOR inhibitors are not. IGF1 receptor (IGF1R) tyro-sine kinase inhibitors also show selectivity for KRAS-mutant lung cancer lines. Combinations of IGF1R and MEK inhibitors resulted in strengthened inhibition of KRAS-mutant lines and also showed improved effectiveness in autochthonous mouse models of Kras-induced NSCLC. PI3K pathway activity is depend-ent on basal IGF1R activity in KRAS-mutant, but not wild-type, lung cancer cell lines. KRAS is needed for both MEK and PI3K pathway activity in KRAS-mutant, but not wild-type, lung cancer cells, whereas acute activation of KRAS causes stimulation of PI3K dependent upon IGF1R kinase activity. Coordinate direct input of both KRAS and IGF1R is thus required to activate PI3K in KRAS-mutant lung cancer cells. SIGNIFICANCE: I...
Inhibition of KRAS-driven tumorigenicity by interruption of an autocrine cytokine circuit
Cancer discovery, 2014
Although the roles of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling in KRAS-driven tumorigenesis are well established, KRAS activates additional pathways required for tumor maintenance, the inhibition of which are likely to be necessary for effective KRAS-directed therapy. Here, we show that the IκB kinase (IKK)-related kinases Tank-binding kinase-1 (TBK1) and IKKε promote KRAS-driven tumorigenesis by regulating autocrine CCL5 and interleukin (IL)-6 and identify CYT387 as a potent JAK/TBK1/IKKε inhibitor. CYT387 treatment ablates RAS-associated cytokine signaling and impairs Kras-driven murine lung cancer growth. Combined CYT387 treatment and MAPK pathway inhibition induces regression of aggressive murine lung adenocarcinomas driven by Kras mutation and p53 loss. These observations reveal that TBK1/IKKε promote tumor survival by activating CCL5 and IL-6 and identify concurrent inhibition of TBK1/IKKε, Janus-activated kinase (JAK), and MEK sig...
Targeting the undruggable oncogenic KRAS: the dawn of hope
JCI Insight
Introduction KRAS is a frequently mutated proto-oncogene that drives epithelial-mesenchymal transition, which leads to tumorigenesis mainly in the lung, colon, and pancreas (1, 2). KRAS belongs to the human RAS gene family that encodes three small GTPases (NRAS, HRAS, and KRAS) that cycle between GTP-bound active and GDP-bound inactive states. KRAS is located on the inner leaflet of the plasma membrane, and active KRAS transduces extracellular signals from receptor tyrosine kinases (RTKs) to downstream signaling pathways, thus controlling cell proliferation, differentiation, transformation, and apoptosis (3). The GTP/GDP molecular switch takes place upon translocation of GEFs and GAPs toward the proximity of KRAS (4). The mutations in the GTP-binding site confer resistance to GTP hydrolysis by GAPs, resulting in constitutively active KRAS (5). Hyperactive KRAS induces oncogenic transformation by upregulating downstream signaling pathways, including PI3K/AKT/mTOR, RAF/ MEK/ERK, MAPK/ERK, and RALGEF/RAL (6). Although RAS proteins exhibit some structural homology and share similar functional and biochemical properties, the oncogenic potential of each RAS isoform varies by the tissue, codon, substitution type, and mutation frequency. More than 80% of mutations in KRAS occur at codon 12, found prevalently as G12D substitution in 70% of pancreatic ductal adenocarcinoma (PDAC) (7) and in almost 50% of colorectal carcinoma (CRC) cases (8). On the other hand, G12C is harbored more frequently in non-small cell lung carcinoma (NSCLC) and is present in approximatively 40% of metastatic lung adenocarcinoma cases (9). From a clinical perspective, KRAS mutants are attractive potential therapeutic targets (10). Thus, numerous efforts have been made over the last 30 years to inhibit mutant KRAS with small molecules. However, attempts to develop GTP analog inhibitors have been challenged by the structural properties of the GTP-binding pocket, high homology between RAS proteins, high affinity between GTP and KRAS, and high concentration of GTP in cells in vivo (11, 12). Alternatively, intensive investigations have been made toward targeting downstream KRAS effectors, including the RAS-binding domain of RAF, the MAPK pathway effector kinases MEK and ERK, and mTOR of the PI3K/AKT pathway (see refs. 12-15 for recent reviews on efforts targeting these pathways). KRAS mutations are the drivers of various cancers, including non-small cell lung cancer, colon cancer, and pancreatic cancer. Over the last 30 years, immense efforts have been made to inhibit KRAS mutants and oncogenic KRAS signaling using inhibitors. Recently, specific targeting of KRAS mutants with small molecules revived the hopes for successful therapies for lung, pancreatic, and colorectal cancer patients. Moreover, advances in gene editing, protein engineering, and drug delivery formulations have revolutionized cancer therapy regimens. New therapies aim to improve immune surveillance and enhance antitumor immunity by precisely targeting cancer cells harboring oncogenic KRAS. Here, we review recent KRAS-targeting strategies, their therapeutic potential, and remaining challenges to overcome. We also highlight the potential synergistic effects of various combinatorial therapies in preclinical and clinical trials.
Because of the refractory nature of mutant KRAS lung adenocarcinoma (LUAD) to current therapies, identification of new molecular targets is essential. Genes with a prognostic role in mutant KRAS LUAD have proven to be potential molecular targets for therapeutic development. Here we determine the clinical, functional, and mechanistic role of inhibitor of differentiation-1 (Id1) in mutant KRAS LUAD. Analysis of LUAD cohorts from TCGA and SPORE showed that high expression of Id1 was a marker of poor survival in patients harboring mutant, but not wild-type KRAS. Abrogation of Id1 induced G 2-M arrest and apoptosis in mutant KRAS LUAD cells. In vivo, loss of Id1 strongly impaired tumor growth and maintenance as well as liver metastasis, resulting in improved survival. Mechanistically, Id1 was regulated by the KRAS oncogene through JNK, and loss of Id1 resulted in downregulation of elements of the mitotic machinery via inhibition of the transcription factor FOSL1 and of several kinases within the KRAS signaling network. Our study provides clinical, functional, and mechanistic evidence underscoring Id1 as a critical gene in mutant KRAS LUAD and warrants further studies of Id1 as a therapeutic target in patients with LUAD. Significance: These findings highlight the prognostic significance of the transcriptional regulator Id1 in KRAS-mutant lung adenocarcinoma and provide mechanistic insight into how it controls tumor growth and metastasis.