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Abstract A25: Synthetic lethal CRISPR-Cas9 screen imply an oncogenic role for FBXW7 mutations in colon cancer
Mutations in tumour suppressors and un-druggable oncogenes dominate the landscape of cancer driver genes. Only a minority of colon cancers have mutations in druggable cancer drivers, such as PIK3CA. Conversely, mutations in tumour suppressors such as APC and TP53 are frequent, as are mutations in the notoriously difficult to drug KRAS target. There is an urgent need for new therapeutics to target tumours driven by these mutations: immune checkpoint approaches are likely to only prove effective in the fraction of patients whose tumours bear high mutation loads, which is colon cancer may be restricted to the minority of mism...
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Moore, J. D., Hudson, C., Russell, P., Tiwana, G., Walter, D., Wiggins, C. M., Yarker, J. Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research

Dasatinib/ARID1A Synthetic Lethality in OCCC
New targeted approaches to ovarian clear cell carcinomas (OCCC) are needed, given the limited treatment options in this disease and the poor response to standard chemotherapy. Using a series of high-throughput cell-based drug screens in OCCC tumor cell models, we have identified a synthetic lethal (SL) interaction between the kinase inhibitor dasatinib and a key driver in OCCC, ARID1A mutation. Imposing ARID1A deficiency upon a variety of human or mouse cells induced dasatinib sensitivity, both in vitro and in vivo, suggesting that this is a robust synthetic lethal interaction. The sensitivity of ARID1A-deficient cells to ...
Source: Molecular Cancer Therapeutics - July 4, 2016 Category: Cancer & Oncology Authors: Miller, R. E., Brough, R., Bajrami, I., Williamson, C. T., McDade, S., Campbell, J., Kigozi, A., Rafiq, R., Pemberton, H., Natrajan, R., Joel, J., Astley, H., Mahoney, C., Moore, J. D., Torrance, C., Gordan, J. D., Webber, J. T., Levin, R. S., Shokat, K. Tags: Small Molecule Therapeutics Source Type: research

Abstract C131: 'KRAS addiction an artifact of 2D culture? Inhibitors of the mut-KRAS NSCLC 3D growth
Conclusion: Variable enhanced growth dependence on mut-KRAS ("addiction") is seen in 2D but not 3D. Potent and specific inhibition of mut-KRAS cell line growth by CNK1 PH-domain inhibitors is considerably more robust in 3D culture suggesting a novel approach to inhibit mut-KRAS effect on cancer growth.Citation Format: D. Lynn Kirkpatrick, Roisin Delaney, Geoff Grandjean, Assael Madrigal, Martin Indarte, Mike Scott, Garth Powis. ‘KRAS addiction’ an artifact of 2D culture? Inhibitors of the mut-KRAS NSCLC 3D growth. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and ...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Kirkpatrick, D. L., Delaney, R., Grandjean, G., Madrigal, A., Indarte, M., Scott, M., Powis, G. Tags: New Molecular Targets: Poster Presentations - Proffered Abstracts Source Type: research

MCL-1 Is a Key Determinant of Breast Cancer Cell Survival
Hyperexpression of antiapoptotic BCL-2 family proteins allows cells to survive despite the receipt of signals that would ordinarily induce their deletion, a facet frequently exploited by tumors. Tumors addicted to the BCL-2 family proteins for survival are now being targeted therapeutically. For example, navitoclax, a BCL-2/BCL-XL/BCL-W inhibitor, is currently in phase I/II clinical trials in numerous malignancies. However, the related family member, MCL-1, limits the efficacy of navitoclax and other chemotherapeutic agents. In the present study, we identify breast cancer cell lines that depend upon MCL-1 for survival and ...
Source: Molecular Cancer Therapeutics - August 5, 2015 Category: Cancer & Oncology Authors: Xiao, Y., Nimmer, P., Sheppard, G. S., Bruncko, M., Hessler, P., Lu, X., Roberts-Rapp, L., Pappano, W. N., Elmore, S. W., Souers, A. J., Leverson, J. D., Phillips, D. C. Tags: Small Molecule Therapeutics Source Type: research