RT Journal Article
SR Electronic
T1 Abstract B14: Human Mut T homolog 1 (MTH1) as a novel facilitator of KRAS-driven lung cancer
JF Molecular Cancer Research
JO Mol Cancer Res
FD American Association for Cancer Research
SP B14
OP B14
DO 10.1158/1557-3125.RASONC14-B14
VO 12
IS 12 Supplement
A1 Patel, Asmita
A1 Halvorsen, Katherine
A1 Balkan, Wayne
A1 Cohen, Alexander
A1 Reiner, Teresita
A1 Robbins, David
A1 Nguyen, Dao
A1 Rai, Priyamvada
YR 2014
UL http://mcr.aacrjournals.org/content/12/12_Supplement/B14.abstract
AB Non-small cell lung carcinoma (NSCLC), a chemoresistant form of lung cancer, is characterized by oncogenic KRAS mutations that confer multiple tumor-promoting traits. Several of these traits are mediated by oncogene-induced reactive oxygen species (ROS). However, oncogenic ROS also produce DNA damage, a major effector of tumor suppressor mechanisms. We previously reported overexpression of the mammalian 8-oxo-dGTP triphosphatase, human MutT Homolog 1 (MTH1), inhibits RAS oncogene-induced senescence (OIS) and any associated DNA damage without substantially affecting ROS levels. Here we report that MTH1 expression is elevated in NSCLC tumors relative to adjacent normal tissue, particularly in tumors with high KRAS expression. We show that MTH1 overexpression facilitates transformation of lung epithelial cells by oncogenic KRAS. We further report that MTH1 suppression in NSCLC cell lines reduces proliferation and tumorigenicity either via DNA strand break-induced elevation of the p53/p21 pathway or by inhibition of Akt activation in p53-nonfunctional tumor cells. Collectively our results indicate MTH1 as a novel potential chemotherapeutic target in NSCLC with activating KRAS mutations. Citation Format: Asmita Patel, Katherine Halvorsen, Wayne Balkan, Alexander Cohen, Teresita Reiner, David Robbins, Dao Nguyen, Priyamvada Rai. Human Mut T homolog 1 (MTH1) as a novel facilitator of KRAS-driven lung cancer. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B14. doi: 10.1158/1557-3125.RASONC14-B14