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• W4361945128 abstract "<div>Abstract<p><b>Purpose:</b> Head and neck squamous cell carcinomas exhibit variable sensitivity to inhibitors of the PI3K/mTOR pathway, an important target of genomic alterations in this cancer type. The mitogen-activated protein kinase kinase (MEK)/ERK/activator protein 1 (AP-1) and nuclear factor-κB (NF-κB) pathways are also frequently co-activated, but their roles in resistance mechanisms to PI3K/mTOR inhibitors and as therapeutic targets in head and neck squamous cell carcinoma (HNSCC) are not well defined.</p><p><b>Experimental Design:</b> We determined the IC₅₀s of dual PI3K/mTOR inhibitor PF-05212384 (PF-384) by XTT assays in 14 HNSCC lines with PI3K/Akt/mTOR cascade alterations. In two resistant models, we further characterized the molecular, cellular, and <i>in vivo</i> attributes and effects of combining PF-384 with MEK inhibitor PD-0325901 (PD-901).</p><p><b>Results:</b> PF-384 IC₅₀s varied between 0.75 and 133 nmol/L in 14 HNSCC lines with overexpression or mutations of <i>PIK3CA</i>, and sensitivity correlated with increased phospho-AKT(T308/S473). In resistant UMSCC-1 and -46 models, PF-384 increased G₀-/G₁-phase accumulation but weakly induced sub-G₀ cell death. PF-384 inhibited direct targets of PI3K/mTOR, but incompletely attenuated co-activated ERK and UMSCC-1 xenograft growth <i>in vivo</i>. PD-901 strongly inhibited MEK/ERK targets, and the combination of PF-384 and PD-901 inhibited downstream NF-κB and AP-1 transactivation, and IL8 and VEGF production <i>in vitro</i>. PD-901 potently inhibited tumor growth alone and with PF384, enhanced antiproliferative, apoptotic, and anti-angiogenesis activity <i>in vivo</i>.</p><p><b>Conclusions:</b> PI3K/mTOR inhibitor PF-384 exhibits variable activity in a panel of HNSCC cell lines with differing <i>PIK3CA</i> expression and mutation status. MEK inhibitor PD-901 overcomes resistance and enhances antitumor effects observed with PF-384 <i>in vivo</i>. <i>Clin Cancer Res; 21(17); 3946–56. ©2015 AACR</i>.</p></div>" @default.
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• W4361945128 date "2023-03-31" @default.
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• W4361945128 title "Data from MEK Inhibitor PD-0325901 Overcomes Resistance to PI3K/mTOR Inhibitor PF-5212384 and Potentiates Antitumor Effects in Human Head and Neck Squamous Cell Carcinoma" @default.
• W4361945128 doi "https://doi.org/10.1158/1078-0432.c.6523433" @default.
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