In:
Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 8, No. 12_Supplement ( 2009-12-10), p. B140-B140
Kurzfassung:
The phosphoinositide 3-kinase (PI3K) signalling pathway is activated in a broad spectrum of human cancers. Activation of this pathway often occurs indirectly by somatic aberrations of receptor tyrosine kinases, or directly by mutations in PI3K genes, such as PIK3CA. GSK2126458 is a novel, orally administered inhibitor of wild type phosphoinositide 3-kinase alpha (PI3K) and the common activation mutants of p110 found in human cancers that has recently entered Phase I clinical trials. In order to determine histological and genetic profiles of patients that are more likely to gain clinical benefit from GSK2126458, the compound was tested in a 3-day continuous exposure proliferation assay on a panel of 198 genetically characterized human cancer cell lines derived from a diversity of tissue types. Cells originating from bladder, breast, and ovarian cancers are most responsive based on growth inhibition metrics (gIC50's). Breast cancer cell lines harboring activating mutations of PIK3CA are associated with increased levels of response (p = 0.027); an observation which was validated in an independent cohort of 53 breast cell lines (p = 0.021). While colon cancers exhibit an intermediate level of sensitivity compared to other tumor types, specific exon 5 G12/13 hotspot mutations of the KRAS gene are predictive of decreased cellular response (p = 0.025). Additionally, a comparison of these cell line proliferation data to a similarly-assayed panel of 19 compounds of diverse target class shows that while the overall pattern of cellular response to GSK2126458 resembles other inhibitors or the PI3K/AKT/mTOR pathway, distinctions emerge that correlate with pathway targeting strategy. For example, while breast cancers are preferentially responsive to GSK2126458 and other inhibitors of this pathway, cell lines harboring PTEN mutations are less responsive to GSK2126458 than to compounds directly targeting AKT. Collectively these data suggest a unique profile for GSK2126458 among compounds that inhibit the PI3K/AKT/mTOR pathway. Positive predictors of response, such as PIK3CA mutations in breast cancer, may identify patients who are most likely to benefit from GSK2126458. The use of this predictor to select patients has the potential to reduce the size of a clinical registration trial for GSK2126458 by approximately 25%, thereby limiting cost and accelerating the development of this compound. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B140.
Materialart:
Online-Ressource
ISSN:
1535-7163
,
1538-8514
DOI:
10.1158/1535-7163.TARG-09-B140
Sprache:
Englisch
Verlag:
American Association for Cancer Research (AACR)
Publikationsdatum:
2009
ZDB Id:
2062135-8
SSG:
12
