The phosphatidylinositol-3-kinase inhibitor PX-866 overcomes resistance to the epidermal growth factor receptor inhibitor gefitinib in A-549 human non–small cell lung cancer xenografts

Abstract

Epidermal growth factor receptor (EGFR) inhibitors such as gefitinib show antitumor activity in a subset of non -small cell lung cancer (NSCLC) patients having mutated EGFR. Recent work shows that phosphatidylinositol-3-kinase (PI3-K) is coupled to the EGFR only in NSCLC cell lines expressing ErbB-3 and that EGFR inhibitors do not inhibit PI3-K signaling in these cells. The central role PI3-K plays in cell survival suggests that a PI3-K inhibitor offers a strategy to increase the antitumor activity of EGFR inhibitors in resistant NSCL tumors that do not express ErbB-3. We show that PX-866, a PI3-K inhibitor with selectivity for p110A, potentiates the antitumor activity of gefitinib against even large A-549 NSCL xenografts giving complete tumor growth control in the early stages of treatment. A-549 xenograft phospho-Akt was inhibited by PX-866 but not by gefitinib. A major toxicity of PX-866 administration was hyperglycemia with decreased glucose tolerance, which was reversed upon cessation of treatment. The decreased glucose tolerance caused by PX-866 was insensitive to the AMP-activated protein kinase inhibitor metformin but reversed by insulin and by the peroxisome proliferator-activated receptor-; activator pioglitazone. Prolonged PX-866 administration also caused increased neutrophil counts. Thus, PX-866, by inhibiting PI3-K signaling, may have clinical use in increasing the response to EGFR inhibitors such as gefitinib in patients with NSCLC and possibly in other cancers who do not respond to EGFR inhibition. [Mol Cancer Ther 2005;4(9):1349 -57]

The ERBB3 receptor in cancer and cancer gene therapy

“…PX866, an inhibitor of the p110α catalytic subunit of PI3K, potentiated the antitumor activity of gefitinib against large A549 xenografts, giving complete tumor growth control in the early stages of treatment. 424 Additive effects of another PI3K inhibitor, LY294002, with gefitinib were also noted in H460 lung cancer cells. 421 These results suggest pathways to PI3K activation in addition to that controlled by EGFR.…”

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

“…In parallel with their preclinical use, the scaffolds of wortmannin and LY294002 have been the subjects of intense lead optimization efforts directed at improving upon the pharmaceutical limitations of the parent compounds. Thus, using wortmannin as a starting point, broad-spectrum PI3K inhibitors with improved pharmaceutical properties and therapeutic indexes such as PWT-458 (compound 3, Figure 2; Yu et al, 2005) and PX-866 (compound 4, Figure 2; Ihle et al, 2005;Howes et al, 2007) have been reported. PWT-458 is a PEGylated derivative of wortmannin that has a higher therapeutic index in preclinical animal models compared to the parent compound.…”

Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia

“…Relatively few in vivo studies have been conducted to demonstrate its efficacy on the inhibition of growth of cancer xenogratfs, but some severe side effects, such as dry and scaly skin, appeared in treated mice. 41 Clearly, the use of nonselective PI3K inhibitors, such as the recently described wortmannin derivative PX-866, 168 is likely to be associated with undesirable side effects (e.g. hyperglycemia) because of the many important physiological targets of this lipid kinase.…”