scholarly journals Evidence that synthetic lethality underlies the mutual exclusivity of oncogenic KRAS and EGFR mutations in lung adenocarcinoma

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Arun M Unni ◽  
William W Lockwood ◽  
Kreshnik Zejnullahu ◽  
Shih-Queen Lee-Lin ◽  
Harold Varmus
Keyword(s):  
Synthetic Lethality ◽  
Human Cancer ◽  
Mapk Signaling ◽  
Egfr Mutations ◽  
Mutual Exclusivity ◽  
Human Cancer Cell Lines ◽  
Activating Mutations ◽  
Oncogenic Mutations ◽  
Lung Adenocarcinomas ◽  
Dying Cells

Human lung adenocarcinomas (LUAD) contain mutations in EGFR in ∼15% of cases and in KRAS in ∼30%, yet no individual adenocarcinoma appears to carry activating mutations in both genes, a finding we have confirmed by re-analysis of data from over 600 LUAD. Here we provide evidence that co-occurrence of mutations in these two genes is deleterious. In transgenic mice programmed to express both mutant oncogenes in the lung epithelium, the resulting tumors express only one oncogene. We also show that forced expression of a second oncogene in human cancer cell lines with an endogenous mutated oncogene is deleterious. The most prominent features accompanying loss of cell viability were vacuolization, other changes in cell morphology, and increased macropinocytosis. Activation of ERK, p38 and JNK in the dying cells suggests that an overly active MAPK signaling pathway may mediate the phenotype. Together, our findings indicate that mutual exclusivity of oncogenic mutations may reveal unexpected vulnerabilities and therapeutic possibilities.

scholarly journals How Cancer Genomics Drives Cancer Biology: Does Synthetic Lethality Explain Mutually Exclusive Oncogenic Mutations?

2016 ◽  
Author(s):  
Harold Varmus ◽  
Arun M. Unni ◽  
William W. Lockwood
Keyword(s):  
Cancer Biology ◽  
Large Scale ◽  
Cancer Genomics ◽  
Synthetic Lethality ◽  
Mutual Exclusivity ◽  
Physiological Basis ◽  
Oncogenic Mutations ◽  
Mutational Pattern ◽  
Cancer Multiple ◽  
Lung Adenocarcinomas

AbstractLarge-scale analyses of cancer genomes are revealing patterns of mutations that suggest biologically significant ideas about many aspects of cancer, including carcinogenesis, classification, and preventive and therapeutic strategies. Among those patterns is “mutual exclusivity”, a phenomenon observed when two or more mutations that are commonly observed in samples of a type of cancer are not found combined in individual tumors. We have been studying a striking example of mutual exclusivity: the absence of co-existing mutations in theKRASandEGFRproto-oncogenes in human lung adenocarcinomas, despite the high individual frequencies of such mutations in this common type of cancer. Multiple lines of evidence suggest that toxic effects of the joint expression ofKRASandEGFRmutant oncogenes, rather than loss of any selective advantages conferred by a second oncogene that operates through the same signaling pathway, are responsible for the observed mutational pattern. We discuss the potential for understanding the physiological basis of such toxicity, for exploiting it therapeutically, and for extending the studies to other examples of mutual exclusivity.

scholarly journals Lung Adenocarcinoma From East Asian Never-Smokers Is a Disease Largely Defined by Targetable Oncogenic Mutant Kinases

2010 ◽  
Vol 28 (30) ◽  
pp. 4616-4620 ◽  
Author(s):  
Yihua Sun ◽  
Yan Ren ◽  
Zhaoyuan Fang ◽  
Chenguang Li ◽  
Rong Fang ◽  
...  
Keyword(s):  
East Asian ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
Single Institution ◽  
Pik3ca Mutations ◽  
Oncogenic Mutations ◽  
Oncogenic Driver ◽  
Never Smokers ◽  
Lung Adenocarcinomas ◽  
Concurrent Analysis

Purpose To determine the proportion of lung adenocarcinomas from East Asian never-smokers who harbor known oncogenic driver mutations. Patients and Methods In this surgical series, 52 resected lung adenocarcinomas from never-smokers (< 100 cigarettes in a lifetime) at a single institution (Fudan University, Shanghai, China) were analyzed concurrently for mutations in EGFR, KRAS, NRAS, HRAS, HER2, BRAF, ALK, PIK3CA, TP53 and LKB1. Results Forty-one tumors harbored EGFR mutations, three harbored EML4-ALK fusions, two harbored HER2 insertions, and one harbored a KRAS mutation. All mutations were mutually exclusive. Thus, 90% (47 of 52; 95% CI, 0.7896 to 0.9625) of lung adenocarcinomas from never-smokers were found to harbor well-known oncogenic mutations in just four genes. No BRAF, NRAS, HRAS, or LKB1 mutations were detected, while 15 had TP53 mutations. Four tumors contained PIK3CA mutations, always together with EGFR mutations. Conclusion To our knowledge, this study represents the first comprehensive and concurrent analysis of major recurrent oncogenic mutations found in a large cohort of lung adenocarcinomas from East Asian never-smokers. Since drugs are now available that target mutant EGFR, HER2, and ALK, respectively, this result indicates that prospective mutation testing in these patients should successfully assign a targeted therapy in the majority of cases.

scholarly journals Functional Characterization of OXYL, A SghC1qDC LacNAc-specific Lectin from The Crinoid Feather Star Anneissia Japonica

Marine Drugs ◽  
2019 ◽  
Vol 17 (2) ◽  
pp. 136 ◽  
Author(s):  
Imtiaj Hasan ◽  
Marco Gerdol ◽  
Yuki Fujii ◽  
Yasuhiro Ozeki
Keyword(s):  
Human Cancer ◽  
Functional Characterization ◽  
Mapk Signaling ◽  
Carbohydrate Binding ◽  
Human Cancer Cell Lines ◽  
Intronless Genes ◽  
Feather Star

We identified a lectin (carbohydrate-binding protein) belonging to the complement 1q(C1q) family in the feather star Anneissia japonica (a crinoid pertaining to the phylum Echinodermata). The combination of Edman degradation and bioinformatics sequence analysis characterized the primary structure of this novel lectin, named OXYL, as a secreted 158 amino acid-long globular head (sgh)C1q domain containing (C1qDC) protein. Comparative genomics analyses revealed that OXYL pertains to a family of intronless genes found with several paralogous copies in different crinoid species. Immunohistochemistry assays identified the tissues surrounding coelomic cavities and the arms as the main sites of production of OXYL. Glycan array confirmed that this lectin could quantitatively bind to type-2 N-acetyllactosamine (LacNAc: Galβ1-4GlcNAc), but not to type-1 LacNAc (Galβ1-3GlcNAc). Although OXYL displayed agglutinating activity towards Pseudomonas aeruginosa, it had no effect on bacterial growth. On the other hand, it showed a significant anti-biofilm activity. We provide evidence that OXYL can adhere to the surface of human cancer cell lines BT-474, MCF-7, and T47D, with no cytotoxic effect. In BT-474 cells, OXYL led to a moderate activation of the p38 kinase in the MAPK signaling pathway, without affecting the activity of caspase-3. Bacterial agglutination, anti-biofilm activity, cell adhesion, and p38 activation were all suppressed by co-presence of LacNAc. This is the first report on a type-2 LacNAc-specific lectin characterized by a C1q structural fold.

scholarly journals A high-content screen identifies the vulnerability of MYC-overexpressing cells to dimethylfasudil

2019 ◽  
Author(s):  
Jing Zhang ◽  
Shenqiu Zhang ◽  
Qiong Shi ◽  
Thaddeus D. Allen ◽  
Fengming You ◽  
...  
Keyword(s):  
Cell Lines ◽  
Synthetic Lethality ◽  
Human Cancer ◽  
Lethal Effect ◽  
Reversible Inhibitor ◽  
Synthetic Lethal Interaction ◽  
Synthetic Lethal ◽  
Human Cancer Cell Lines ◽  
Direct Targeting ◽  
Approved Drugs

AbstractA synthetic lethal effect arises when a cancer-associated change introduces a unique vulnerability to cancer cells that makes them unusually susceptible to a drug’s inhibitory activity. The synthetic lethal approach is attractive because it enables targeting of cancers harboring specific genomic alterations, the products of which may have proven refractory to direct targeting. An example is cancer driven by overexpression of MYC. Here, we conducted a high-content screen for compounds that are synthetic lethal to elevated MYC using a small-molecule library to identify compounds that are closely related to, or are themselves, regulatory-approved drugs. The screen identified dimethylfasudil, a potent and reversible inhibitor of Rho-associated kinases ROCK1 and ROCK2. Close analogs of dimethylfasudil are used clinically to treat neurologic and cardiovascular disorders. The synthetic lethal interaction was conserved in rodent and human cell lines and could be observed with activation of either MYC or its paralog MYCN. The synthetic lethality seems specific to MYC overexpressing cells as it could not be substituted by a variety of oncogenic manipulations and synthetic lethality was diminished by RNAi-mediated depletion of MYC in human cancer cell lines. Collectively, these data support investigation of the use of dimethylfasudil as a drug that is synthetic lethal for malignancies that specifically overexpress MYC.Significance StatementSynthetic lethal targeting of tumors overexpressing MYC holds promise for attacking aggressive malignancies. Here we describe a synthetic lethal interaction between dimethylfasudil and overexpression of MYC. Uniquely, this novel synthetic lethal interaction points toward an opportunity for synthetic lethality with a molecule likely to harbor favorable drug-like properties that enable systemic use.

scholarly journals A high-content screen identifies the vulnerability of MYC-overexpressing cells to dimethylfasudil

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0248355
Author(s):  
Jing Zhang ◽  
Shenqiu Zhang ◽  
Qiong Shi ◽  
Thaddeus D. Allen ◽  
Fengming You ◽  
...  
Keyword(s):  
Cell Lines ◽  
Synthetic Lethality ◽  
Human Cancer ◽  
Lethal Effect ◽  
Reversible Inhibitor ◽  
Synthetic Lethal ◽  
Human Cancer Cell Lines ◽  
Small Molecule Library ◽  
Direct Targeting ◽  
Approved Drugs

A synthetic lethal effect arises when a cancer-associated change introduces a unique vulnerability to cancer cells that makes them unusually susceptible to a drug’s inhibitory activity. The synthetic lethal approach is attractive because it enables targeting of cancers harboring specific genomic or epigenomic alterations, the products of which may have proven refractory to direct targeting. An example is cancer driven by overexpression of MYC. Here, we conducted a high-content screen for compounds that are synthetic lethal to elevated MYC using a small-molecule library to identify compounds that are closely related to, or are themselves, regulatory-approved drugs. The screen identified dimethylfasudil, a potent and reversible inhibitor of Rho-associated kinases, ROCK1 and ROCK2. Close analogs of dimethylfasudil are used clinically to treat neurologic and cardiovascular disorders. The synthetic lethal interaction was conserved in rodent and human cell lines and could be observed with activation of either MYC or its paralog MYCN. The synthetic lethality seems specific to MYC overexpressing cells as it could not be substituted by a variety of oncogenic manipulations and synthetic lethality was diminished by RNAi-mediated depletion of MYC in human cancer cell lines. Collectively, these data support investigation of the use of dimethylfasudil as a drug that is synthetic lethal for malignancies that specifically overexpress MYC.

Sign in / Sign up

Export Citation Format

Share Document