Research Describes Novel Tumor-Promoting Adaptation in Non-Small Cell Lung Carcinoma
A collaborative Miller School study led by Priyamvada Rai, Ph.D., assistant professor of medicine in the Division of Gerontology and Geriatric Medicine, describes a novel therapeutic target in RAS-driven lung cancer, a common but untreatable carcinoma.
The study, “MutT Homolog 1 (MTH1) maintains multiple KRAS-driven pro-malignant pathways,” published July 14 online ahead of print in Oncogene, a Nature Publishing Group journal, describes a critical role for MTH1, a protein which sanitizes oxidized DNA precursors, in facilitating tumor formation by activated KRAS, the most commonly mutated oncogene in human cancers. The study specifically focused on KRAS-driven non-small cell lung carcinoma (NSCLC), a highly aggressive and treatment-resistant form of lung cancer.
“Using human tumor tissue samples from patients at the Sylvester Comprehensive Cancer Center, we found that MTH1 expression is particularly high in KRAS-mutant NSCLC,” said Rai, who is senior author. “We decided to investigate whether MTH1 played any causal role in this lung malignancy.”
Rai and her team suspected that MTH1 was a protective response against the DNA damage invoked by the large amounts of oxidants produced by KRAS oncogene-sustaining NSCLC cells to activate tumor-driving molecular pathways, and that MTH1 inhibition would increase such growth-suppressive oxidative DNA damage. However, this was only found to occur in NSCLC tumor cells that retained function of a major tumor suppressor protein called p53. Because 50 percent of tumors lack functional p53, Rai and her team then examined whether inhibiting MTH1 had any effect in the absence of p53.
“It turns out that MTH1 inhibition also was able to reduce tumor formation by NSCLC cells that lacked p53,” Rai said. “However, the mechanism by which this occurred was independent of oxidative DNA damage, which was unexpected to us.”
In the functional p53-lacking cells, the researchers found that MTH1 was acting as a molecular rheostat for KRAS oncogene levels. If MTH1 levels were high, oncogenic RAS and associated oxidant levels could be robustly maintained, and their downstream malignant signaling could occur at full capacity to drive tumor cell division. But if MTH1 was inhibited, only NSCLC cells with low KRAS oncogene levels, and thus sustaining a lesser degree of pro-malignant oxidant signaling, could continue to grow, reducing their cancer-forming potential.
To date, Rai says, no drug has been able to effectively target the RAS oncogene.
“Our study indicates that targeting MTH1 instead may be sufficient to inhibit RAS-driven tumors such as NSCLC,” said Rai, adding that she and her team are developing transgenic animal models for pre-clinical studies.
Other Miller School authors of the study are David Robbins, Ph.D., professor of surgery; Dao Nguyen, M.D., professor of surgery, the B. and Donald Carlin Chair in Thoracic Surgical Oncology, Chief of the Thoracic Surgery Section of the Division of Cardiothoracic Surgery and Co-Chair of the Lung Cancer Site Disease Group at Sylvester; Wayne Balkan, Ph.D., research assistant professor of medicine; and Carlos Perez-Stable, Ph.D., research associate professor of medicine.