Abstract 1442: Identifying the molecular basis by which βIII-tubulin promotes tumor cell survival and drug resistance in non-small cell lung cancer

Abstract

Abstract Lung cancer is the leading cause of cancer-related mortality worldwide with the most common sub-type, non-small cell lung carcinoma (NSCLC), accounting for >80% of cases. Despite advances in treatments, 5-year survival rates for this disease remain dismal. Advanced NSCLC responds poorly to current therapy and the mechanisms underlying its resistance and aggressive nature are not well defined. Microtubules form a component of the cell cytoskeleton and alterations in the expression of microtubule proteins are increasingly correlated with more aggressive and treatment-refractory cancers. βIII-tubulin is a neuronal-specific isotype that is aberrantly expressed in a range of cancers including NSCLC, and has been found to be correlated with reduced patient survival. Our group has recently demonstrated that βIII-tubulin contributes to activation of the PI3K/AKT cell-survival pathway in NSCLC cells[1]. One of the key negative regulators of this pathway is the tumor suppressor PTEN. PTEN can inhibit cell growth, migration and invasion, and a loss of PTEN function is often associated with cancer progression through AKT hyperactivation. Here, using forced-genetics cell models, we show that AKT activation is reduced by βIII-tubulin knockdown, and that re-expression of βIII-tubulin restores these levels in NSCLC cells. Interestingly, we also found that βIII-tubulin knockdown resulted in increased PTEN mRNA along with altered levels of Snail-1/β-catenin, suggesting a possible role for βIII-tubulin in regulating the transcriptional pathway of the PTEN tumor suppressor. Building on these findings, we also identified, through a high-throughput cell-based drug screen, several receptor tyrosine kinase inhibitors that synergize with βIII-tubulin knockdown to reduce NSCLC cell proliferation and tumoroid growth. Together, our data demonstrate an important role for βIII-tubulin in modulating the activation and/or expression levels of signaling proteins which form part of a major pro-survival pathway in NSCLC. In addition, our results suggest that inhibition of βIII-tubulin in combination with drugs that target multiple kinases may offer a novel therapeutic strategy for the treatment of NSCLC to improve patient outcomes. [1] McCarroll et al., TUBB3/betaIII-tubulin acts through the PTEN/AKT signaling axis to promote tumorigenesis and anoikis resistance in non-small cell lung cancer. Cancer Research. 2015;75:415-425. Citation Format: Simon Brayford, Wee Siang Teo, Amelia Parker, Laura McVeigh, Joshua A. McCarroll, Maria Kavallaris. Identifying the molecular basis by which βIII-tubulin promotes tumor cell survival and drug resistance in non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1442.