Therapeutic Targeting Of Ras Mutant Cancers

The KRAS oncogene is believed to be the most common single nucleotide variant oncogene in human cancer. Historically, efforts to target KRAS and the other RAS GTPases have struggled. More recently, efforts have focused on identifying and exploiting features unique to specific oncogenic mutations. This has led to the first FDA approval for a RAS targeted therapy. This new agent is a covalent inhibitor that reacts with the cysteine residue created by a codon 12 glycine to cysteine (G12C) mutation within KRAS. Mutant-specific strategies may also exist for other KRAS single nucleotide variants, and recent studies provide examples and mechanisms.

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. Overview of the history and development of efforts to pharmacologically inhibit RAS. Discussion of the biochemistry and biology of different RAS mutant proteins and how this might be effectively leveraged in the development of anti-RAS therapies. Up-to-date reviews of the cutting-edge approaches to develop new anti-RAS pharmacologics.

Ras proteins are key molecular switches in cell signaling pathways that, when activated, trigger cell growth and division. Mutations that produce abnormally active Ras proteins are common in human cancers, particularly those of the pancreas, lung, and colon. These cancers can be difficult to treat because Ras oncoproteins have long been considered 'undruggable.' Written and edited by experts in the field, this collection from Cold Spring Harbor Perspectives in Medicine covers the recent progress that has been made in understanding Ras biology, how Ras activation leads to tumorigenesis, and ways in which oncogenic Ras signaling may be targeted therapeutically. The contributors review the biochemical characteristics of the different Ras isoforms (HRAS, KRAS, and NRAS), their main effectors and signaling pathways, and the mutations that lead to their constitutive activation. Recent work showing that some Ras oncoproteins may be effectively inhibited by small molecules is covered, as is work on alternative targets (e.g., enzymes that catalyze posttranslational modifications of Ras) and inhibitors (e.g., nucleic acids). The authors also discuss how organoids and mouse models are being used to study tumor progression and therapeutic efficacy. This volume is therefore essential reading for all cancer biologists, cell and molecular biologists, and pharmacologists concerned with understanding and treating Ras-driven cancers.

Since 1982, Ras proteins have been the subject of intense research investigation by the biomedical research community. The wide interest in Ras has been stimulated for three key reasons. This book features chapters contributed by leading investigators in the field that highlight the current state-of-the art in Ras biochemistry, structure and biology. This book is an excellent reference for students in the biomedical sciences and for investigators in the field.

Since the last edition of this book, major advances have been made in our understanding of key pathways that control tumor progression. This has led to the development of new anticancer agents that have the ability to block the activity of proteins involved in neoplastic cell development and proliferation. Targeted Therapies in Oncology, Second Edition provides a concise timely panorama of existing targeted therapies and progress into future anticancer treatments. These therapies notably include: Targeted agents of immune checkpoints Signal-transduction inhibitors Antiangiogenic agents Vascular-disrupting agents Apoptosis modulators Stem cell inhibitors Tumor profiling for drug development The book emphasizes the biology behind this new class of drugs as well as the clinical achievements obtained. The contributors to this volume stand at the cutting edge of cancer research and treatment around the world.

This, the first of two volumes on personalized medicine in lung cancer, touches on the core issues related to the understanding of lung cancer—statistics and epidemiology of lung cancer—along with the incidence of lung cancer in non-smokers. A major focus of this volume is the state of current therapies against lung cancer—immune, targeted therapies against EGFR TKIs, KRAS, ALK, angiogenesis; the associated challenges, especially resistance mechanisms; and recent progress in targeted drug development based on metal chemistry. Chapters are written by some of the leading experts in the field, who provide a better understanding of lung cancer, the factors that make it lethal, and current research focused on developing personalized treatment plans. With a unique mix of topics, this volume summarizes the current state-of-knowledge on lung cancer and the available therapies.

Drug Repurposing in Cancer Therapy: Approaches and Applications provides comprehensive and updated information from experts in basic science research and clinical practice on how existing drugs can be repurposed for cancer treatment. The book summarizes successful stories that may assist researchers in the field to better design their studies for new repurposing projects. Sections discuss specific topics such as in silico prediction and high throughput screening of repurposed drugs, drug repurposing for overcoming chemoresistance and eradicating cancer stem cells, and clinical investigation on combination of repurposed drug and anticancer therapy. Cancer researchers, oncologists, pharmacologists and several members of biomedical field who are interested in learning more about the use of existing drugs for different purposes in cancer therapy will find this to be a valuable resource. Presents a systematic and up-to-date collection of the research underpinning the various drug repurposing approaches for a quick, but in-depth understanding on current trends in drug repurposing research Brings better understanding of the drug repurposing process in a holistic way, combining both basic and clinical sciences Encompasses a collection of successful stories of drug repurposing for cancer therapy in different cancer types