Journal
EXPERT OPINION ON THERAPEUTIC TARGETS
Volume 17, Issue 5, Pages 507-531Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1517/14728222.2013.764990
Keywords
AKT; MEK; mTOR; nononcogene addiction; PI3K; Raf; Ras; RNAi-based therapy; synthetic lethality; targeted therapy
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Funding
- National Cancer Institute [CA112102, CA164245, CA141908]
- Department of Defense [PC100093, CA110396]
- Raymond and Beverly Sackler Fund for the Arts and Sciences
- Karin Grunebaum Cancer Research Foundation
- Melanoma Research Alliance
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Introduction: The Ras proteins (K-Ras, N-Ras, and H-Ras) are GTPases that function as molecular switches for a variety of critical cellular activities and their function is tightly and temporally regulated in normal cells. Oncogenic mutations in the RAS genes, which create constitutively-active Ras proteins, can result in uncontrolled proliferation or survival in tumor cells. Areas covered: The paper discusses three therapeutic approaches targeting the Ras pathway in cancer: i) Ras itself, ii) Ras downstream pathways, and iii) synthetic lethality. The most adopted approach is targeting Ras downstream signaling, and specifically the PI3K-AKT-mTOR and Raf-MEK pathways, as they are frequently major oncogenic drivers in cancers with high Ras signaling. Although direct targeting of Ras has not been successful clinically, newer approaches being investigated in preclinical studies, such as RNA interference-based and synthetic lethal approaches, promise great potential for clinical application. Expert opinion: The challenges of current and emerging therapeutics include the lack of tumor specificity and their limitation to those cancers which are dependent on aberrant Ras signaling for survival. While the newer approaches have the potential to overcome these limitations, they also highlight the importance of robust preclinical studies and bidirectional translational research for successful clinical development of Ras-related targeted therapies.
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