Abstract
Abstract Resistance to many anti-cancer agents has been attributed to increased PI3K/PTEN pathway signaling. Hence, inhibitors of the pathway have potential utility in combination with these therapies. To investigate chemotherapy drug sensitivities downstream of mutant PIK3CA in a controlled and patient-relevant context we utilized human non-tumorigenic MCF10A parental and isogenic knock-in cell lines that harbor a common activating PIK3CA kinase domain mutation (H1047R). We found the mutant cells to be least sensitive to anti-mitotic drugs, but the resistance could be overcome in combination with GDC-0941, a Class I PI3K inhibitor currently being evaluated in clinical trials. To understand the mechanism of resistance we analyzed microarray data for expression of known anti-mitotic resistance genes. We found that a subset of tubulin isoforms were increased with PI3K pathway signaling, but were reduced with GDC-0941 treatment. The changes in mRNA expression were confirmed at the protein level and were extended to additional cell lines. RNAi knockdown of TUBB2, the isoform we found to be most influenced by PI3K pathway signaling, increased the sensitivity of both parental and H1047R clones to anti-mitotic drugs, but did not influence GDC-0941 potency. Thus, reduced expression of the target increases the potency of the anti-mitotic drug. Overall, these findings suggest a mechanism of action for anti-mitotic drugs in combination with inhibitors of PI3K. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 298.
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call