RAS: Past, Present, and Future

1st Edition, Volume 153 - January 29, 2022
Editors: John P. O'Bryan, Gary Piazza
Language: English
Hardback ISBN:
9 7 8 - 0 - 1 2 - 8 2 4 4 8 5 - 2
eBook ISBN:
9 7 8 - 0 - 1 2 - 8 2 4 4 8 6 - 9

Advances in Cancer Research, volume 153 provides a timely review of the biology, biochemistry, and current approaches to therapeutically target the RAS oncoprotein, the most freque… Read more

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Advances in Cancer Research, volume 153 provides a timely review of the biology, biochemistry, and current approaches to therapeutically target the RAS oncoprotein, the most frequently mutated oncogene family in human cancers. 2021 saw the approval of the first direct RAS inhibitor (sotorasib) for use in treating non-small cell lung cancers harboring KRAS(G12C) mutations. The successful approval and use of this drug highlights that the once “undruggable” RAS is indeed pharmacologically tractable. This volume provides an overview of efforts to develop additional approaches to therapeutically target oncogenic RAS. In addition, the reader will find excellent reviews on the history and research efforts to understand the biochemistry and oncogenic activity of RAS in human cancers.

Cover image
Title page
Table of Contents
Copyright
Contributors
Preface
Chapter One: A brief history of RAS and the RAS Initiative
Abstract
1: Discovery of v-Ha-RAS, v-Ki-RAS and N-RAS
2: Discovery of GAPs
3: Discovery of RAS GEFs
4: Discovery of RAF kinases and their relationship to RAS
5: The RAS Initiative at Frederick National Laboratories
References
Chapter Two: Not all RAS mutations are equal: A detailed review of the functional diversity of RAS hot spot mutations
Abstract
1: Introduction
2: RAS mutational frequencies in cancer
3: RAS mutational frequencies across cancer
4: All RAS mutant proteins are not equal
5: RAS effector interactions and mutational frequencies
6: Intrinsic nucleotide (GDP and GTP) dissociation and GTP hydrolysis
7: GEFs and GAPs
8: Conclusions
Acknowledgments
References
Chapter Three: Drug targeting opportunities en route to Ras nanoclusters
Abstract
1: Introduction
2: Ras processing and trafficking
3: Trafficking-factors and -chaperones of Ras
4: Organization of Ras in specific plasma membrane lipid domains and nanocluster
5: Lipid domain and Ras nanocluster modulating factors
6: Concluding remarks
References
Chapter Four: Targeting the ERK mitogen-activated protein kinase cascade for the treatment of KRAS-mutant pancreatic cancer
Abstract
1: Introduction
2: KRAS: The predominant RAS gene mutated in human cancer
3: Targeting KRAS for cancer treatment: Direct inhibition of RAS
4: Targeting KRAS for cancer treatment: A focus on RAS effector signaling
5: The ERK MAPK signaling network
6: ERK feedback inhibition and the Goldilock Principle: A “just right” level of ERK signaling supports cancer growth
7: Inhibition of the RAF-MEK-ERK cascade: Promises and challenges
8: ERK regulation of a diverse phosphoproteome and transcriptome
9: MYC: The critical determinant for ERK-dependent cancer growth?
10: KRAS, ERK, MYC and metabolism: An Achilles heel for KRAS-mutant PDAC?
References
Chapter Five: Pan-RAS inhibitors: Hitting multiple RAS isozymes with one stone
Abstract
1: Introduction
2: PAN-RAS inhibitors
3: Discussion
4: Conclusion
References
Chapter Six: Targeting RAS oncogenesis with SOS1 inhibitors
Abstract
1: Introduction: RAS proteins and their Guanine Nucleotide Exchange Factors (GEFs)
2: SOS1 as a molecular target for cancer therapy
3: Discovery of the hydrophobic pocket on SOS1
4: More binders for the hydrophobic pocket
5: The long way from activators to inhibitors
6: Molecular basis for SOS1 activation versus inhibition
7: Selectivity against SOS2 and other RasGEFs
8: Activity of SOS1 inhibitors in cellular assays
9: SOS1 inhibition affects RAS mutations with residual intrinsic GTPase activity
10: SOS1 inhibitors in RASopathies
11: SOS1 inhibitors in combination therapy
12: Clinical studies
13: Conclusions
References
Chapter Seven: Inhibition of SHP2 as an approach to block RAS-driven cancers
Abstract
1: Introduction
2: Biology of RTK/RAS signaling
3: General understanding of RAS-driven cancer and treatment
4: The biological and oncogenic role of SHP2
5: SHP2 inhibitors as potential therapies in RAS-driven cancers
6: Conclusions and perspectives
References
Chapter Eight: Targeting the “undruggable” RAS with biologics
Abstract
1: Introduction
2: Anti-RAS biologics
3: Targeting RAS using peptide-PROTACs: A new frontier for RAS inhibition
4: Conclusion and future outlook
References
Chapter Nine: Unraveling and targeting RAS-driven metabolic signaling for therapeutic gain
Abstract
1: Introduction
2: Glycolysis
3: Mitochondrial signaling and dynamics
4: Autophagy
5: Lipid scavenging and metabolism
6: Macropinocytosis
7: Concluding remarks
Acknowledgments
References
Chapter Ten: The RASopathies: Biology, genetics and therapeutic options
Abstract
1: Introduction
2: Neurofibromatosis type 1 (NF1) and related syndromes
3: Legius syndrome
4: Noonan syndrome and related syndromes
5: Noonan-related syndromes
6: Costello syndrome
7: Cardiofaciocutaneous syndrome
8: Gingival fibromatosis
9: Capillary malformation-arteriovenous malformation syndrome
10: Future directions
References

John P. O'Bryan

Dr. O'Bryan received his Ph.D. from the University of North Carolina at Chapel Hill. He then pursued postdoctoral studies at the Samuel Lunenfeld Institute in Toronto, Canada and the University of North Carolina at Chapel Hill. Dr. O'Bryan then established his independent research program at the National Institute of Environmental Health Science, NIH in Research Triangle Park before being recruited to the University of Illinois at Chicago. In 2018, he was recruited to the NCI-Designated Hollings Cancer Center at MUSC where he is Professor in the Department of Cell and Molecular Pharmacology and Experimental Therapeutics and Director of Graduate Studies. In addition, Dr. O'Bryan has a joint appointment as a Research Health Scientist at the Ralph H. Johnson VA Medical Center. Dr. O’Bryan’s research interests have centered on understanding the regulation of cell signaling pathways involved in normal and pathophysiological conditions, particularly cancer. His current research is focused on defining vulnerabilities in RAS that can be exploited for the development of new therapeutics for the treatment of RAS mutant cancers. His research is supported by grants from the National Institutes of Health, the Veterans Administration, and various private foundations.

Affiliations and expertise

Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Hollings Cancer Center, Medical University of South Carolina, and Research Health Scientist, Ralph H. Johnson VA Medical Center, South Carolina USA

Gary Piazza

Dr. Piazza received his Ph.D. from The University of Alabama at Birmingham in 1986 and pursued postdoctoral studies at the Fox Chase Cancer Center and later at Brown University. Dr. Piazza also gained research experience in the pharmaceutical industry with the Proctor and Gamble Company and later with Cell Pathways Inc. Dr. Piazza returned to academic research in 2001 as the Director of Pharmacology at the Institute for Drug Development in San Antonio and later as a Principal Scientist at Southern Research in Birmingham where he established an independent research program funded by the NCI. In 2011, Dr. Piazza joined the University of South Alabama Mitchell Cancer Institute to hold the appointments of Professor of Oncologic Sciences and Pharmacology; Leader, Chemoprevention and Experimental Therapeutics; and Chief of the Drug Discovery Research Center up until 2021. Currently Dr. Piazza serves as the Head of the Department of Drug Discovery and Development and as Director of the Cancer Research Center in the Harrison School of Pharmacy at Auburn University. His research interests are in the field of cancer drug discovery. His research team has discovered and developed several promising drug candidates including a novel class of pan-RAS inhibitors with high potency and selectivity for cancer cells harboring mutant RAS. Dr. Piazza has been continuously funded by the NIH since 2004 and is a co-founder of ADT Pharmaceuticals LLC in Alabama.

Affiliations and expertise

W.W. Walker Endowed Professor, Department Head, Drug Discovery and Development , Director, Harrison School of Pharmacy Cancer Research Center, Auburn University, Auburn, AL, USA