Selumetinib in patients receiving standard pemetrexed and platinum-based chemotherapy for advanced or metastatic KRAS wildtype or unknown non-squamous non-small cell lung cancer: A randomized, multicenter, phase II study. Canadian Cancer Trials Group (CCTG) IND.219

Melosky, Barbara; Bradbury, Penelope Ann; Tu, Dongsheng; Florescu, Marie; Reiman, Anthony; Nicholas, Garth; Basappa, Naveen S.; Rothenstein, J.; Goffin, John R.; Laurie, Scott A.; Wheatley‐Price, Paul; Leighl, Natasha B.; Goss, Glenwood D.; Reaume, M. Neil; Butts, Charles; Murray, Nevin; Card, Cynthia; Ko, Jenny J.; Blais, Normand; Gray, Samantha; Lui, Hongbo; Brown-Walker, Pamela; Kaurah, Pardeep; Prentice, Leah M; Seymour, Lesley

doi:10.1016/j.lungcan.2019.04.027

Cited by 22 publications

(11 citation statements)

References 18 publications

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“…The well-established oncogenic role of the MEK-ERK pathway [62][63][64][65] has made this pathway a primary drug target for numerous cancers [66,67]. The efficacy of MEK inhibitors as monotherapy or in combinatorial treatment strategies was supported by several pre-clinical or clinical trials in several primary or metastatic settings [68][69][70][71][72][73]. Interestingly, a higher frequency of RASA1 mutations was found in the high-risk SCC cohort and cell lines, which is a negative regulator of the RAF-MEK-ERK pathway.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Gene Signature for Squamous Cell Carcinoma with a Higher Risk for Treatment Failure and Accelerated MEK-ERK Pathway Activity

Feng

Wang

Herpel

et al. 2021

Cancers

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Squamous cell carcinoma (SCC) is the most prevalent histological type of human cancer, including head and neck squamous cell carcinoma (HNSCC). However, reliable prognostic gene signatures for SCC and underlying genetic and/or epigenetic principles are still unclear. We identified 37 prognostic candidate genes by best cutoff computation based on survival in a pan-SCC cohort (n = 1334) of The Cancer Genome Atlas (TCGA), whose expression stratified not only the pan-SCC cohort but also independent HNSCC validation cohorts into three distinct prognostic subgroups. The most relevant prognostic genes were prioritized by a Least Absolute Shrinkage and Selection Operator Cox regression model and were used to identify subgroups with high or low risks for unfavorable survival. An integrative analysis of multi-omics data identified FN1, SEMA3A, CDH2, FBN1, COL5A1, and ADAM12 as key nodes in a regulatory network related to the prognostic phenotype. An in-silico drug screen predicted two MEK inhibitors (Trametinib and Selumetinib) as effective compounds for high-risk SCC based on the Cancer Cell Line Encyclopedia, which is supported by a higher p-MEK1/2 immunohistochemical staining of high-risk HNSCC. In conclusion, our data identified a molecular classifier for high-risk HNSCC as well as other SCC patients, who might benefit from treatment with MEK inhibitors.

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Section: Discussionmentioning

confidence: 99%

Prognostic Gene Signature for Squamous Cell Carcinoma with a Higher Risk for Treatment Failure and Accelerated MEK-ERK Pathway Activity

Feng

Wang

Herpel

et al. 2021

Cancers

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show abstract

“… Active signaling pathway Functions during detachment Activated in cancer metastasis Efficacy of targeting inhibitors in metastatic patient or animal Integrin/FAK/SFKs pathway Protecting cells from anoikis and activating protective autophagy Activated in a variety of metastasis, including breast cancer, lung cancer, melanoma, colorectal cancer, prostate cancer, glioblastoma, liver cancer [ 96 ] Melanoma [ 176 ], breast cancer [ 177 ], colorectal cancer [ 178 ], ovarian cancer [ 179 ], hepatocellular carcinoma [ 180 ], non-small cell lung cancer [ 181 ], etc. Ras/ERK signaling pathway Attenuating cellular stress and enhancing anoikis resistance Colorectal cancer [ 132 , 135 ], germ-cell tumors [ 136 ], multiple myeloma [ 137 ], skin cancer [ 138 , 139 ], melanoma [ 140 ] and lung cancer [ 141 ] Thyroid cancer [ 142 , 143 ], non-small cell lung cancer [ 144 , 182 ], melanoma [ 145 , 183 , 184 ], colorectal cancer [ 185 ], biliary tract cancer [ 186 ] PI3K/ATK signaling pathway Enhancing nutrients uptake, decreasing ROS production and inhibiting anoikis Colorectal cancer [ 135 , 146 ], melanoma [ 147 , 148 ], prostate cancer [ 149 ], lung cancer, breast cancer and renal cell carcinomas [ 150 ] Endometrial cancer [ 155 ], breast cancer [ 156 , 187 – 189 ], gastric cancer [ 190 ], cervical carcinoma [ 191 ...…”

Section: The Implication Of Anchorage-independent Survival In Cancer Metastasismentioning

confidence: 99%

Comprehensive understanding of anchorage-independent survival and its implication in cancer metastasis

et al. 2021

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Detachment is the initial and critical step for cancer metastasis. Only the cells that survive from detachment can develop metastases. Following the disruption of cell–extracellular matrix (ECM) interactions, cells are exposed to a totally different chemical and mechanical environment. During which, cells inevitably suffer from multiple stresses, including loss of growth stimuli from ECM, altered mechanical force, cytoskeletal reorganization, reduced nutrient uptake, and increased reactive oxygen species generation. Here we review the impact of these stresses on the anchorage-independent survival and the underlying molecular signaling pathways. Furthermore, its implications in cancer metastasis and treatment are also discussed.

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“…Several drugs inhibiting Ras, Raf or MEK, including selumetinib, are currently under clinical investigation. 84,85…”

Section: Molecular Basis For Sex Differences In Lung Cancermentioning

confidence: 99%

Role of sex hormones in lung cancer

Fuentes

Rodriguez

Silveyra

2021

Exp Biol Med (Maywood)

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Lung cancer represents the world’s leading cause of cancer deaths. Sex differences in the incidence and mortality rates for various types of lung cancers have been identified, but the biological and endocrine mechanisms implicated in these disparities have not yet been determined. While some cancers such as lung adenocarcinoma are more commonly found among women than men, others like squamous cell carcinoma display the opposite pattern or show no sex differences. Associations of tobacco product use rates, susceptibility to carcinogens, occupational exposures, and indoor and outdoor air pollution have also been linked to differential rates of lung cancer occurrence and mortality between sexes. While roles for sex hormones in other types of cancers affecting women or men have been identified and described, little is known about the influence of sex hormones in lung cancer. One potential mechanism identified to date is the synergism between estrogen and some tobacco compounds, and oncogene mutations, in inducing the expression of metabolic enzymes, leading to enhanced formation of reactive oxygen species and DNA adducts, and subsequent lung carcinogenesis. In this review, we present the literature available regarding sex differences in cancer rates, associations of male and female sex hormones with lung cancer, the influence of exogenous hormone therapy in women, and potential mechanisms mediated by male and female sex hormone receptors in lung carcinogenesis. The influence of biological sex on lung disease has recently been established, thus new research incorporating this variable will shed light on the mechanisms behind the observed disparities in lung cancer rates, and potentially lead to the development of new therapeutics to treat this devastating disease.

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Selumetinib in patients receiving standard pemetrexed and platinum-based chemotherapy for advanced or metastatic KRAS wildtype or unknown non-squamous non-small cell lung cancer: A randomized, multicenter, phase II study. Canadian Cancer Trials Group (CCTG) IND.219

Cited by 22 publications

References 18 publications

Prognostic Gene Signature for Squamous Cell Carcinoma with a Higher Risk for Treatment Failure and Accelerated MEK-ERK Pathway Activity

Prognostic Gene Signature for Squamous Cell Carcinoma with a Higher Risk for Treatment Failure and Accelerated MEK-ERK Pathway Activity

Comprehensive understanding of anchorage-independent survival and its implication in cancer metastasis

Role of sex hormones in lung cancer

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