Reference Detail

Ref Type

Journal Article

PMID

(21998291)

Authors

Wallin JJ, Edgar KA, Guan J, Berry M, Prior WW, Lee L, Lesnick JD, Lewis C, Nonomiya J, Pang J, Salphati L, Olivero AG, Sutherlin DP, O'Brien C, Spoerke JM, Patel S, Lensun L, Kassees R, Ross L, Lackner MR, Sampath D, Belvin M, Friedman LS

Title

GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K pathway.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	10	12	2011 Dec	2426-36	Mol Cancer Ther

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Apitolisib	Apitolisib	10	3

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Apitolisib		GDC-0980	mTOR Inhibitor 51 PI3K Inhibitor (Pan) 40	Apitolisib (GDC-0980) is an inhibitor of both PI3K and mTOR kinases, resulting in decreased phosphorylation of PI3K/Akt/mTOR pathway markers, which may lead to inhibition of tumor growth and tumor regression (PMID: 21998291, PMID: 30914027).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References