Targeting KRAS-mutant non-small cell lung cancer: challenges and opportunities

Zhang, Jun; Park, Dongkyoo; Shin, Dong M.; Deng, Xingming

doi:10.1093/abbs/gmv118

Cited by 17 publications

(19 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In clinical trials FTIs did not show activity in NSCLC, and they have never been tested in a defined KRAS mutant population [ 10 , 50 ]. A possible explanation for the FTIs failure may be the presence of an alternative modification, the geranylgeranylation, that is another process to localize protein to the membrane (Figure 2 ) [ 54 ].…”

Section: Resultsmentioning

confidence: 99%

Implications of KRAS mutations in acquired resistance to treatment in NSCLC

Rofi

Restante

et al. 2017

Oncotarget

View full text Add to dashboard Cite

RationaleKRAS is the most common and, simultaneously, the most ambiguous oncogene implicated in human cancer. Despite KRAS mutations were identified in Non Small Cell Lung Cancers (NSCLCs) more than 20 years ago, selective and specific inhibitors aimed at directly abrogating KRAS activity are not yet available. Nevertheless, many therapeutic approaches have been developed potentially useful to treat NSCLC patients mutated for KRAS and refractory to both standard chemotherapy and targeted therapies.The focus of this review will be to provide an overview of the network related to the intricate molecular KRAS pathways, stressing on preclinical and clinical studies that investigate the predictive value of KRAS mutations in NSCLC patients.Materials and MethodsA bibliographic search of the Medline database was conducted for articles published in English, with the keywords KRAS, KRAS mutations in non-small cell lung cancer, KRAS and tumorigenesis, KRAS and TKIs, KRAS and chemotherapy, KRAS and monoclonal antibody, KRAS and immunotherapy, KRAS and drugs, KRAS and drug resistance.

show abstract

Section: Resultsmentioning

confidence: 99%

Implications of KRAS mutations in acquired resistance to treatment in NSCLC

Rofi

Restante

et al. 2017

Oncotarget

View full text Add to dashboard Cite

show abstract

“…Mutant KRAS activates over a dozen downstream targets to assert its protumorigenic effects and the RAF/MEK/ERK pathway is among one of the most wellcharacterized (15). In fact, many approaches to targeting mutant KRAS cancers involve the utilization of MEK/ERK inhibitors (27)(28)(29)(42)(43)(44). Our work revealed that KRAS regulates SREBP1 expression via MEK/ERK activation.…”

Section: Discussionmentioning

confidence: 80%

“…Previous studies showed that MEK/ERK regulate translation (26). Therefore, we treated 293T cells transfected with SREBP1 and KRAS with the MEK inhibitor AZD6244 (27)(28)(29). MEK inhibition greatly blunted the effect of KRAS on SREBP1 protein expression compared to vehicle control (Figure 3a).…”

Section: Oncogenic Kras Regulates Srebp1 Protein Expression Via Mek1/mentioning

confidence: 89%

SREBP1 regulates mitochondrial metabolism in oncogenicKRASexpressing NSCLC

Ruiz

Montal

Haley

et al. 2020

Preprint

View full text Add to dashboard Cite

Cancer cells require extensive metabolic reprogramming in order to provide the bioenergetics and macromolecular precursors needed to sustain a malignant phenotype.Mutant KRAS is a driver oncogene that is well known for its ability to regulate the ERK and PI3K signaling pathways. However, it is now appreciated that KRAS can promote tumor growth via upregulation of anabolic metabolism. We recently showed that oncogenic KRAS promotes a gene expression program of de novo lipogenesis in nonsmall cell lung cancer (NSCLC). To define the mechanism(s) responsible, we focused on the lipogenic transcription factor SREBP1. We observed that KRAS increases SREBP1 expression and genetic knockdown of SREBP1 significantly inhibited cell proliferation of mutant KRAS-expressing cells. Unexpectedly, lipogenesis was not significantly altered in cells subject to SREBP1 knockdown. Carbon tracing metabolic studies showed a significant decrease in oxidative phosphorylation and RNA-seq data revealed a significant decrease in mitochondrial encoded subunits of the electron transport chain (ETC). Taken together, these data support a novel role, distinct from lipogenesis, of SREBP1 on mitochondrial function in mutant KRAS NSCLC.3

show abstract

“…v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) is a very important oncogene for the initiation of cancer [1]. It is usually found to be mutated in different types of cancer, particularly in colorectal cancers (CRCs), pancreatic cancer (PC), and lung cancer [4][5][6]. Concerning KRAS, different chemicals such as polychlorinated biphenyls (PCBs), certain antidiabetic drugs, and pesticides may be leading causes of KRAS mutations, and such mutations increase the expression of K-Ras protein in different tissues, leading to high cellular proliferation and finally carcinogenesis [7][8][9].…”

mentioning

confidence: 99%

Introductory Chapter: Interactions between Environmental Chemicals and KRAS Oncogene in Different Cancers - Special Focus on Colorectal, Pancreatic, and Lung Cancers

Erkekoğlu¹

2019

Oncogenes and Carcinogenesis

View full text Add to dashboard Cite

Introduction v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) is an oncogene. The KRAS gene is located on the twelfth chromosome and belongs to the Ras family of oncogenes. These proteins play important roles in cell division, cell differentiation, and apoptotic cell death. Induction of KRAS with different environmental chemicals leads to high expression of K-Ras protein, which in turn causes high cellular proliferation. These cascade of events finally initiate certain types of cancers, particularly colorectal (CRC), pancreatic, and lung cancers. High calorie intake, diets rich in meat and fat, smoking, and alcohol consumption are the major risk factors of CRCs, and it was estimated that in CRC, mutated KRAS has an incidence of ∼50%. Exposure to certain environmental chemicals [organochlorine insecticides such as DDT and its metabolite dichlorodiphenyltrichloroethylene (DDE); herbicides such as EPTC and pendimethalin; N-nitrosamines; polychlorinated biphenyls (PCBs); benzene] and drugs (anti-diabetics drugs) can also contribute to the increased incidence of PC throughout the world. It was stated that in adenocarcinomas of the pancreas, mutated KRAS has an incidence of ∼70-90%. Lung cancer is the leading cause of deaths worldwide. KRAS gene mutations are much more common in long-term tobacco smokers with lung cancer when compared to nonsmokers. KRAS gene mutations are observed in 15-25% of all lung cancer cases, being more frequent in whites vs. Asian populations. Lung cancers with KRAS gene mutations typically indicate a poor prognosis and are associated with resistance to several cancer treatments. This chapter mainly focuses on KRAS, interactions between environmental chemicals, and KRAS oncogene in different cancers, particularly in colorectal, pancreatic, and lung cancers. Most oncogenes are expressed as proto-oncogenes, involved in cell growth and proliferation or inhibition of apoptosis. If there are chemical, physical, or biological factors that cause mutations in such genes promoting cellular growth, these genes are mostly upregulated and cellular proliferation increases [1]. The cascade of events leading to proliferation usually predisposes the cell to cancer. In this case,

show abstract

Targeting KRAS-mutant non-small cell lung cancer: challenges and opportunities

Cited by 17 publications

References 74 publications

Implications of KRAS mutations in acquired resistance to treatment in NSCLC

Implications of KRAS mutations in acquired resistance to treatment in NSCLC

SREBP1 regulates mitochondrial metabolism in oncogenicKRASexpressing NSCLC

Introductory Chapter: Interactions between Environmental Chemicals and KRAS Oncogene in Different Cancers - Special Focus on Colorectal, Pancreatic, and Lung Cancers

Contact Info

Product

Resources

About