Molecular Target Class Is Predictive of In vitro Response Profile

Abstract

Preclinical cellular response profiling of tumor models has become a cornerstone in the development of novel cancer therapeutics. As efforts to predict clinical efficacy using cohorts of in vitro tumor models have been successful, expansive panels of tumor-derived cell lines can recapitulate an "all comers" efficacy trial, thereby identifying which tumors are most likely to benefit from treatment. The response profile of a therapy is most often studied in isolation; however, drug treatment effect patterns in tumor models across a diverse panel of compounds can help determine the value of unique molecular target classes in specific tumor cohorts. To this end, a panel of 19 compounds was evaluated against a diverse group of cancer cell lines (n = 311). The primary oncogenic targets were a key determinant of concentration-dependent proliferation response, as a total of five of six, four of four, and five of five phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, insulinlike growth factor-I receptor (IGF-IR), and mitotic inhibitors, respectively, clustered with others of that common target class. In addition, molecular target class was correlated with increased responsiveness in certain histologies.

Comparison of the effects of the PI3K/mTOR inhibitors NVP-BEZ235 and GSK2126458 on tamoxifen-resistant breast cancer cells

“…6 As PIK3CA mutations have been found in 18-40% of human breast cancer, it was hypothesized that these mutation could be responsible for the deregulation in the signaling pathway and consequently these patients would be most suitable for PI3K/ mTOR pathway inhibition. 12 The luminal-epithelial like MCF-7 cell line, a recognized model for estrogen receptor positive breast cancer, harbors a PI3KCA helical E545K mutation (www.sanger.…”

“…5 Patients with tumors exhibiting aberrant PI3K/Akt/mTOR signaling may benefit from therapy targeting specific components of this pathway and some PI3K/Akt/mTOR inhibitors have been reported to be efficacious in breast cancers. 6 NVP-BEZ235 (BEZ235) 7 and GSK2126458 (GSK212) 8 are highly selective and potent small molecule inhibitors that target both multiple class I PI3K isoforms and mTOR kinase activity 7,8 ©2 0 1 1 L a n d e s B i o s c i e n c e .…”

Conserved Molecular Interactions within the HBO1 Acetyltransferase Complexes Regulate Cell Proliferation

“…Nuclear magnetic resonance (NMR) experiments were performed at 25°C on Varian INOVA 600-and 500-MHz spectrometers using pulse field gradients to suppress artifacts and eliminate water signal. 1 H, 15 N heteronuclear single quantum coherence (HSQC) spectra of uniformly 15 N-labeled JADE1 PHD1 and PHD-Zn knuckle-PHD (PZP) (0.1 to 0.2 mM) were recorded as histone tail peptides (synthesized by the University of Colorado at Denver [UCD] Biophysics Core Facility), and unlabeled PHD1 was added stepwise.…”

Targeting of TGFβ signature and its essential component CTGF by miR-18 correlates with improved survival in glioblastoma

“…Previously, we used publicly available microarray data from human cancer cell lines, known as the Wooster data set (Greshock et al 2010), to look for patterns of expression of MIR17HG . Despite its purportedly oncogenic role, we observed a wide range of MIR17HG expression across tumor types, with particularly low expression in glioblastoma multiforme (GBM).…”