ABSTRACT
Elucidation of the mutational landscape of human cancer has progressed rapidly and been accompanied by the development of therapeutics targeting mutant oncogenes. However, a comprehensive mapping of cancer dependencies has lagged behind and the discovery of therapeutic targets for counteracting tumor suppressor gene loss is needed. To identify vulnerabilities relevant to specific cancer subtypes, we conducted a large-scale RNAi screen in which viability effects of mRNA knockdown were assessed for 7,837 genes using an average of 20 shRNAs per gene in 398 cancer cell lines. We describe findings of this screen, outlining the classes of cancer dependency genes and their relationships to genetic, expression, and lineage features. In addition, we describe robust gene-interaction networks recapitulating both protein complexes and functional cooperation among complexes and pathways. This dataset along with a web portal is provided to the community to assist in the discovery and translation of new therapeutic approaches for cancer.
Subject(s)
Neoplasms/genetics , Neoplasms/pathology , RNA Interference , Cell Line, Tumor , Gene Library , Gene Regulatory Networks , Humans , Multiprotein Complexes/metabolism , Neoplasms/metabolism , Oncogenes , RNA, Small Interfering , Signal Transduction , Transcription Factors/metabolismABSTRACT
Tankyrases (TNKS) play roles in Wnt signaling, telomere homeostasis, and mitosis, offering attractive targets for anticancer treatment. Using unbiased combination screening in a large panel of cancer cell lines, we have identified a strong synergy between TNKS and MEK inhibitors (MEKi) in KRAS-mutant cancer cells. Our study uncovers a novel function of TNKS in the relief of a feedback loop induced by MEK inhibition on FGFR2 signaling pathway. Moreover, dual inhibition of TNKS and MEK leads to more robust apoptosis and antitumor activity both in vitro and in vivo than effects observed by previously reported MEKi combinations. Altogether, our results show how a novel combination of TNKS and MEK inhibitors can be highly effective in targeting KRAS-mutant cancers by suppressing a newly discovered resistance mechanism.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Proto-Oncogene Proteins/genetics , Receptor, Fibroblast Growth Factor, Type 2/metabolism , Tankyrases/metabolism , ras Proteins/genetics , Acetamides/administration & dosage , Aminopyridines/administration & dosage , Aniline Compounds/administration & dosage , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cell Line, Tumor , Drug Synergism , Erlotinib Hydrochloride , Feedback, Physiological , Female , Humans , MAP Kinase Kinase Kinases/antagonists & inhibitors , MAP Kinase Kinase Kinases/metabolism , Mice , Mice, Nude , Morpholines/administration & dosage , Mutation , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins p21(ras) , Pyrimidinones/administration & dosage , Quinazolines/administration & dosage , Receptor, Fibroblast Growth Factor, Type 2/antagonists & inhibitors , Signal Transduction , Sulfonamides/administration & dosage , Tankyrases/antagonists & inhibitors , Thiazoles/administration & dosage , Xenograft Model Antitumor AssaysABSTRACT
Personally controlled health records (PCHRs) and patient portals are increasingly being offered by healthcare institutions, employers, insurance companies and commercial entities to allow patients access to their health information. Both applications offer unique services to provide patients with tools to manage their health. While PCHRs allow users ubiquitous, portable, patient controlled access to their health information, traditional patient portals provide provider-tethered applications allowing patients access, but not control of, certain healthcare information, as well as communication and administrative functions, such as secure messaging, appointment management and prescription refill requests, facilitating care at a specific healthcare facility.We describe our approach for the design, content creation, policy development, and implementation of MyChildren's, a unique web-based application leveraging the advantages of both a provider-tethered patient portal and a PCHR to allow patients and their guardians access to the functionality and convenience of a traditional patient portal, as well as the portability and flexibility of a PCHR.
