Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress

Shaw, Alice T.; Winslow, Monte M.; Magendantz, Margaret; Ouyang, Chensi; Dowdle, James A.; Subramanian, Aravind; Lewis, Timothy A.; Maglathin, Rebecca L.; Tolliday, Nicola; Jacks, Tyler

doi:10.1073/pnas.1105941108

Cited by 218 publications

(167 citation statements)

References 33 publications

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“…This causes the down-regulation of growth-promoting signals from tyrosine kinase receptors and this may be the mechanism by which ROS impair growth. In support of this antiproliferative role of ROS, two studies have identified two different ROSinducing compounds from chemical screens that can inhibit the growth of KRAS-transformed 3T3 cells (19) and cancer cells (20). In addition, it was recently shown that the transcription factor Nrf2 (which controls a antioxidant pathway) was required for tumorigenesis in mice by oncogenes such as Kras (21).…”

Section: Discussionmentioning

confidence: 99%

Superoxide dismutase 1 (SOD1) is a target for a small molecule identified in a screen for inhibitors of the growth of lung adenocarcinoma cell lines

Somwar

Erdjument‐Bromage²,

Larsson³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

140

128

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We previously described four small molecules that reduced the growth of lung adenocarcinoma cell lines with either epidermal growth factor receptor (EGFR) or KRAS mutations in a highthroughout chemical screen. By combining affinity proteomics and gene expression analysis, we now propose superoxide dismutase 1 (SOD1) as the most likely target of one of these small molecules, referred to as lung cancer screen 1 (LCS-1). siRNAs against SOD1 slowed the growth of LCS-1 sensitive cell lines; conversely, expression of a SOD1 cDNA increased proliferation of H358 cells and reduced sensitivity of these cells to LCS-1. In addition, SOD1 enzymatic activity was inhibited in vitro by LCS-1 and two closely related analogs. These results suggest that SOD1 is an LCS-1-binding protein that may act in concert with mutant proteins, such as EGFR and KRAS, to promote cell growth, providing a therapeutic target for compounds like LCS-1.

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Section: Discussionmentioning

confidence: 99%

Superoxide dismutase 1 (SOD1) is a target for a small molecule identified in a screen for inhibitors of the growth of lung adenocarcinoma cell lines

Somwar

Erdjument‐Bromage²,

Larsson³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

140

128

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“…In vivo, lanperisone also showed efficacy against tumor growth in a K-Ras-driven mouse model of lung cancer. 12 The exact mechanism responsible for lanperisone-induced ROS generation is not known, but preliminary results suggest that it occurs through the perturbation of voltage-gated ion channels. 11 Sulfasalazine.…”

Section: Morphologymentioning

confidence: 99%

Ferroptosis: process and function

et al. 2016

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Ferroptosis is a recently recognized form of regulated cell death. It is characterized morphologically by the presence of smaller than normal mitochondria with condensed mitochondrial membrane densities, reduction or vanishing of mitochondria crista, and outer mitochondrial membrane rupture. It can be induced by experimental compounds (e.g., erastin, Ras-selective lethal small molecule 3, and buthionine sulfoximine) or clinical drugs (e.g., sulfasalazine, sorafenib, and artesunate) in cancer cells and certain normal cells (e.g., kidney tubule cells, neurons, fibroblasts, and T cells). Activation of mitochondrial voltage-dependent anion channels and mitogen-activated protein kinases, upregulation of endoplasmic reticulum stress, and inhibition of cystine/glutamate antiporter is involved in the induction of ferroptosis. This process is characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS) derived from iron metabolism and can be pharmacologically inhibited by iron chelators (e.g., deferoxamine and desferrioxamine mesylate) and lipid peroxidation inhibitors (e.g., ferrostatin, liproxstatin, and zileuton). Glutathione peroxidase 4, heat shock protein beta-1, and nuclear factor erythroid 2-related factor 2 function as negative regulators of ferroptosis by limiting ROS production and reducing cellular iron uptake, respectively. In contrast, NADPH oxidase and p53 (especially acetylation-defective mutant p53) act as positive regulators of ferroptosis by promotion of ROS production and inhibition of expression of SLC7A11 (a specific light-chain subunit of the cystine/glutamate antiporter), respectively. Misregulated ferroptosis has been implicated in multiple physiological and pathological processes, including cancer cell death, neurotoxicity, neurodegenerative diseases, acute renal failure, drug-induced hepatotoxicity, hepatic and heart ischemia/reperfusion injury, and T-cell immunity. In this review, we summarize the regulation mechanisms and signaling pathways of ferroptosis and discuss the role of ferroptosis in disease.

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“…Nevertheless, limited efforts have been dedicated to dissect the role of combinations of mutations in determining drug response. Among these studies, it is worth mentioning the use of isogenic cell lines to evaluate the influence of KRAS or TP53 status on the sensitivity to (32)(33)(34)(35).…”

Section: Discussionmentioning

confidence: 99%

BRAF V600E Is a Determinant of Sensitivity to Proteasome Inhibitors

Zecchin

Boscaro

Medico

et al. 2013

Molecular Cancer Therapeutics

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A critical step toward defining tailored therapy in patients with cancer is the identification of genetic interactions that may impair-or boost-the efficacy of selected therapeutic approaches. Cell models able to recapitulate combinations of genetic aberrations are important to find drug-genotype interactions poorly affected by the heterogeneous genetics of human tumors. In order to identify novel pharmacogenomic relationships, we employed an isogenic cell panel that reconstructs cancer genetic scenarios. We screened a library of 43 compounds in human hTERT-HME1 epithelial cells in which PTEN or RB1 were silenced in combination with the targeted knockin of cancer-associated mutations in EGFR, KRAS, BRAF, or PIK3CA oncogenes. Statistical analysis and clustering algorithms were applied to display similar drug response profiles and mutation-specific patterns of activity. From the screen, we discovered that proteasome inhibitors show selectivity toward BRAF V600E-mutant cells, irrespective of PTEN or RB1 expression. Preferential targeting of BRAF-mutant cells by proteasome inhibitors was corroborated in a second BRAF V600E isogenic model, as well as in a panel of colorectal cancer cell lines by the use of the proteasome inhibitor carfilzomib. Notably, carfilzomib also showed striking in vivo activity in a BRAF-mutant human colorectal cancer xenograft model. Vulnerability to proteasome inhibitors is dependent on persistent BRAF signaling, because BRAF V600E blockade by PLX4720 reversed sensitivity to carfilzomib in BRAF-mutant colorectal cancer cells. Our findings indicated that proteasome inhibition might represent a valuable targeting strategy in BRAF V600E-mutant colorectal tumors. Mol Cancer Ther; 12(12); 2950-61. Ó2013 AACR.

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Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress

Cited by 218 publications

References 33 publications

Superoxide dismutase 1 (SOD1) is a target for a small molecule identified in a screen for inhibitors of the growth of lung adenocarcinoma cell lines

Superoxide dismutase 1 (SOD1) is a target for a small molecule identified in a screen for inhibitors of the growth of lung adenocarcinoma cell lines

Ferroptosis: process and function

BRAF V600E Is a Determinant of Sensitivity to Proteasome Inhibitors

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