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MutT Homolog 1 (MTH1) maintains multiple KRAS-driven pro-malignant pathways

A Patel¹, D G A Burton¹, K Halvorsen¹

¹Department of Medicine, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA.

|July 16, 2014

Abstract:

Oncogenic RAS promotes production of reactive oxygen species (ROS), which mediate pro-malignant signaling but can also trigger DNA damage-induced tumor suppression. Thus RAS-driven tumor cells require redox-protective mechanisms to mitigate the damaging aspects of ROS. Here, we show that MutT Homolog 1 (MTH1), the mammalian 8-oxodGTPase that sanitizes oxidative damage in the nucleotide pool, is important for maintaining several KRAS-driven pro-malignant traits in a nonsmall cell lung carcinoma (NSCLC) model. MTH1 suppression in KRAS-mutant NSCLC cells impairs proliferation and xenograft tumor formation. Furthermore, MTH1 levels modulate KRAS-induced transformation of immortalized lung epithelial cells. MTH1 expression is upregulated by oncogenic KRAS and correlates positively with high KRAS levels in NSCLC human tumors. At a molecular level, in p53-competent KRAS-mutant cells, MTH1 loss provokes DNA damage and induction of oncogene-induced senescence. In p53-nonfunctional KRAS-mutant cells, MTH1 suppression does not produce DNA damage but reduces proliferation and leads to an adaptive decrease in KRAS expression levels. Thus, MTH1 not only enables evasion of oxidative DNA damage and its consequences, but can also function as a molecular rheostat for maintaining oncogene expression at optimal levels. Accordingly, our results indicate MTH1 is a novel and critical component of oncogenic KRAS-associated malignancy and its inhibition is likely to yield significant tumor-suppressive outcomes in KRAS-driven tumors.

Insights

MutT Homolog 1 (MTH1) is crucial for KRAS-driven lung cancer progression by protecting cells from reactive oxygen species (ROS). Inhibiting MTH1 halts tumor growth and may offer a new therapeutic strategy for KRAS-mutant non-small cell lung carcinoma.

Area of Science:

Oncology
Molecular Biology
Cancer Research

Background:

Oncogenic RAS proteins elevate reactive oxygen species (ROS), which paradoxically promote malignancy while also triggering tumor suppression.
RAS-driven cancer cells necessitate robust redox-protective mechanisms to counteract ROS-induced damage.
MutT Homolog 1 (MTH1), an 8-oxodGTPase, plays a key role in mitigating oxidative damage within the nucleotide pool.

Purpose of the Study:

To investigate the role of MTH1 in maintaining pro-malignant traits driven by KRAS mutations in non-small cell lung carcinoma (NSCLC).
To elucidate the molecular mechanisms by which MTH1 influences KRAS-driven oncogenesis and tumor progression.

Main Methods:

Utilized a non-small cell lung carcinoma (NSCLC) model with KRAS mutations.
Performed MTH1 suppression experiments in KRAS-mutant NSCLC cells and immortalized lung epithelial cells.
Analyzed MTH1 expression in human NSCLC tumors and correlated it with KRAS levels.
Investigated the impact of MTH1 loss on DNA damage, senescence, proliferation, and KRAS expression in p53-competent and p53-nonfunctional cells.

Main Results:

MTH1 suppression impaired proliferation and xenograft tumor formation in KRAS-mutant NSCLC cells.
MTH1 levels were found to modulate KRAS-induced cellular transformation.
MTH1 expression was upregulated by oncogenic KRAS and positively correlated with KRAS levels in human NSCLC.
In p53-competent cells, MTH1 loss induced DNA damage and senescence; in p53-nonfunctional cells, it reduced proliferation and KRAS expression.

Conclusions:

MTH1 is essential for sustaining KRAS-driven pro-malignant phenotypes in NSCLC.
MTH1 functions not only in preventing oxidative DNA damage but also in regulating oncogene expression levels.
MTH1 represents a critical component in KRAS-associated malignancy, suggesting its inhibition as a potential therapeutic strategy for KRAS-driven tumors.

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