GDC-0980 Is a Novel Class I PI3K/mTOR Kinase Inhibitor with Robust Activity in Cancer Models Driven by the PI3K Pathway

Abstract

Alterations of the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway occur broadly in cancer via multiple mechanisms including mutation of the PIK3CA gene, loss or mutation of phosphatase and tensin homolog (PTEN), and deregulation of mammalian target of rapamycin (mTOR) complexes. The dysregulation of this pathway has been implicated in tumor initiation, cell growth and survival, invasion and angiogenesis, thus, PI3K and mTOR are promising therapeutic targets for cancer. We discovered GDC-0980, a selective, potent, orally bioavailable inhibitor of Class I PI3 kinase and mTOR kinase (TORC1/2) with excellent pharmacokinetic and pharmaceutical properties. GDC-0980 potently inhibits signal transduction downstream of both PI3K and mTOR, as measured by pharmacodynamic (PD) biomarkers, thereby acting upon two key pathway nodes to produce the strongest attainable inhibition of signaling in the pathway. Correspondingly, GDC-0980 was potent across a broad panel of cancer cell lines, with the greatest potency in breast, prostate, and lung cancers and less activity in melanoma and pancreatic cancers, consistent with KRAS and BRAF acting as resistance markers. Treatment of cancer cell lines with GDC-0980 resulted in G1 cell-cycle arrest, and in contrast to mTOR inhibitors, GDC-0980 induced apoptosis in certain cancer cell lines, including those with direct pathway activation via PI3K and PTEN. Low doses of GDC-0980 potently inhibited tumor growth in xenograft models including those with activated PI3K, loss of LKB1 or PTEN, and elicited an exposure-related decrease in PD biomarkers. These preclinical data show that GDC-0980 is a potent and effective dual PI3K/mTOR inhibitor with promise for the clinic. Mol Cancer Ther; 10(12); 2426-36. Ó2011 AACR.

Phosphoproteomic characterization of DNA damage response in melanoma cells following MEK/PI3K dual inhibition

“…S1B and Table S1). To confirm that induction of the DDR was not unique to these particular inhibitors, experiments were carried out using combinations of either GDC-0973 and the PI3K/mTOR inhibitor GDC-0980 (19) or GDC-0941 and the BRAF inhibitor PLX-4720 (20). As expected, inhibition of various signaling nodes resulted in a similar extent of PARP cleavage, DDR signaling, and p53/H2AX phosphorylation (Fig.…”

Application and interpretation of current autophagy inhibitors and activators

“…These data suggest a novel function for ceramide in autophagy upregulation. Recent studies show that CH5132799 [55] , GDC-0980 [56] , and GDC-0941 [57] potently inhibit signal transduction downstream of both PI3K and mTOR. However, only the pro-apoptotic mechanisms of these three novel class I PI3K inhibitors have been discussed.…”

NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, enhances the radiosensitivity of human glioma stem cells in vitro

“…This pathway also promotes tumor survival after radiation-induced DNA damage [12] . Dysregulation of this pathway is frequently observed in GBM and occurs via multiple mechanisms, including mutation of the PIK3CA gene [13] , deregulation of mTOR complexes [14] , and loss or mutation of the phosphatase and tensin homolog [15] . Inhibition of this cascade can enhance radiosensitivity of the tumor cells without affecting the normal cells, which is an attractive concept for improving therapeutic outcomes [16] .…”