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Autophagy induction with RAD001 improves chemosensitivity and radiosensitivity in papillary thyroid cancer

Lin, Chi-Iou and Lorch, Jochen and Whang, Edward E and Jiang, Xiaofeng and Price, Brendan D and He, Frank and Du, Jinyan and Carothers, Adelaide M and Nose, Vania and Moore, Francis D Jr and Ruan, Daniel T and Imark, Esther (2010) Autophagy induction with RAD001 improves chemosensitivity and radiosensitivity in papillary thyroid cancer. Molecular Cancer Research, 8 (9). pp. 1217-1226. ISSN 1541-7786

Abstract

Thyroid cancer is the most common endocrine malignancy and is responsible for 60% of deaths from endocrine cancer [Gimm et al., 2001]. Papillary thyroid cancer (PTC) accounts for approximately 80% of thyroid cancers and is associated with favorable patient survival when treated with thyroidectomy, radioactive iodine ablation, and thyroid hormone supplementation [Fassnacht et al., 2009]. However, subgroups of patients with PTC have locally advanced or systemic disease that is not amenable to curative therapy. Doxorubicin is the only FDA approved systemic chemotherapy agent for patients with advanced PTC that does not trap radioactive iodine. However, intrinsic resistance to doxorubicin results in limited efficacy in patients with advanced PTC [Hanna et al., 1999] and it is rarely used clinicaly. Therefore, strategies to improve systemic chemotherapy for advanced PTC are urgently needed.
Autophagy is a highly conserved process that entails the degradation of intracellular components through the lysosomal machinery to regenerate metabolites for energy and growth [Kondo et al., 2005 and Levine et al., 2004]. In many contexts, autophagy promotes cell survival under stressful conditions such as nutrient and growth factor deprivation [Kuma et al., 2004; Lum et al., 2005]. However, excess or prolonged autophagy can lead to an alternative mechanism of programmed cell death, also known as autophagic cell death [Pattingre et al., 2005] [Clarke et al., 1990].
RAD001 (Everolimus), a rapamycin analogue, is an oral mammalian target of rapamycin (mTOR) inhibitor. . mTOR is an intracellular protein that acts as a central regulator of multiple signaling pathways (IGF, EGF, PDGF, VEGF, amino acids) that mediate abnormal growth, proliferation and angiogenesis in cancer1. mTOR is a critical component of the PI3K/AKT pathway, a key signaling pathway that is frequently dysregulated in many cancers and affects proliferation, cancer cell metabolism and angiogenesis.1 It has recently been approved by FDA for the treatment of metastatic renal cell cancer and has shown promising activity in a variety of cancers including neuroendocrine tumors of the pancreas2. Clinical activity of RAD001 in thyroid cancer is unknown and a clinical is under way.
There is accumulating evidence that RAD001stimulates autophagic activity [Easton et al., 2006; Johnson et al., 2007]. Since preliminary data suggests that autophagy inhibition decreases doxorubicin chemosensitivity and radiosensitivity [Lin et al., 2009, in press], we hypothesize that RAD001 can improve chemosensitivity and radiosensitivity in PTC through the activation of autophagy. We found that RAD001 synergistically improves chemosensitivity. Interestingly, autophagy activation in PTC induces Src phosphorylation while Met phosphorylation was reduced.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/1607

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