https://www.cell.com/cell-metabolism/pdf/S1550-4131(15)00621-X.pdf

The Emerging Hallmarks of Cancer Metabolism

The regulation of oxidative stress is an important factor in both tumour development and responses to anticancer therapies. Many signalling pathways that are linked to tumorigenesis can also regulate the metabolism of reactive oxygen species (ROS) through direct or indirect mechanisms. High ROS levels are generally detrimental to cells, and the redox status of cancer cells usually differs from that of normal cells. Because of metabolic and signalling aberrations, cancer cells exhibit elevated ROS levels. The observation that this is balanced by an increased antioxidant capacity suggests that high ROS levels may constitute a barrier to tumorigenesis. However, ROS can also promote tumour formation by inducing DNA mutations and pro-oncogenic signalling pathways. These contradictory effects have important implications for potential anticancer strategies that aim to modulate levels of ROS. In this Review, we address the controversial role of ROS in tumour development and in responses to anticancer therapies, and elaborate on the idea that targeting the antioxidant capacity of tumour cells can have a positive therapeutic impact.

Modulation of oxidative stress as an anticancer strategy.

Tumors reprogram pathways of nutrient acquisition and metabolism to meet the bioenergetic, biosynthetic, and redox demands of malignant cells. These reprogrammed activities are now recognized as hallmarks of cancer, and recent work has uncovered remarkable flexibility in the specific pathways activated by tumor cells to support these key functions. In this perspective, we provide a conceptual framework to understand how and why metabolic reprogramming occurs in tumor cells, and the mechanisms linking altered metabolism to tumorigenesis and metastasis. Understanding these concepts will progressively support the development of new strategies to treat human cancer.

Fundamentals of cancer metabolism

Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism

Despite more than three decades of intensive effort, no effective pharmacological inhibitors of the RAS oncoproteins have reached the clinic, prompting the widely held perception that RAS proteins are 'undruggable'. However, recent data from the laboratory and the clinic have renewed our hope for the development of RAS-inhibitory molecules. In this Review, we summarize the progress and the promise of five key approaches. Firstly, we focus on the prospects of using direct inhibitors of RAS. Secondly, we address the issue of whether blocking RAS membrane association is a viable approach. Thirdly, we assess the status of targeting RAS downstream effector signalling, which is arguably the most favourable current approach. Fourthly, we address whether the search for synthetic lethal interactors of mutant RAS still holds promise. Finally, RAS-mediated changes in cell metabolism have recently been described and we discuss whether these changes could be exploited for new therapeutic directions. We conclude with perspectives on how additional complexities, which are not yet fully understood, may affect each of these approaches.

/pdf/drugging-the-undruggable-ras-mission-possible-25j0sc44dt.pdf

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Papers

Functional genomics reveal that the serine synthesis pathway is essential in breast cancer