KRAS combination strategies: How well aligned is clinical and preclinical research?

Ernest Nadal; Chiara Ambrogio; David Santamaria; Colin R. Lindsay

doi:10.1016/B978-0-443-21861-3.00018-8

KRAS combination strategies: How well aligned is clinical and preclinical research?

Ernest Nadal, Chiara Ambrogio, David Santamaria, Colin R. Lindsay

Division of Cancer Sciences (L5)

Research output: Chapter in Book/Conference proceeding › Chapter › peer-review

Abstract

The discovery and breakthrough of KRAS^G12C inhibitors have been described as “the end of the beginning” for RAS precision medicine. In parallel with development of a new generation of pan-RAS, pan-KRAS, and allele-specific KRAS treatment approaches, a large body of preclinical/clinical data has quickly and comprehensively delineated a multitude of resistance mechanisms to first-generation “OFF-state” inhibitors such as sotorasib and adagrasib. Addressing acquired and adaptive resistance mechanisms will require perseverance and innovation with clinical trial combination approaches, while more preclinical focus is still necessary for understanding intrinsic resistance and resistance conferred by histological transformation. To help process this challenge, this chapter will highlight current disparities/mismatches that exist between clinical and preclinical approaches to RAS translation.

Original language	English
Title of host publication	Ras Drug Discovery
Subtitle of host publication	Past, Present and Future
Publisher	Elsevier Australia
Pages	417-441
Number of pages	25
ISBN (Electronic)	9780443218613
ISBN (Print)	9780443218620
DOIs	https://doi.org/10.1016/B978-0-443-21861-3.00018-8
Publication status	Published - 1 Jan 2025

Keywords

Checkpoint
Combination
Immunotherapy
KRAS
Lung cancer
RAS

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/B978-0-443-21861-3.00018-8

Cite this

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title = "KRAS combination strategies: How well aligned is clinical and preclinical research?",

abstract = "The discovery and breakthrough of KRASG12C inhibitors have been described as “the end of the beginning” for RAS precision medicine. In parallel with development of a new generation of pan-RAS, pan-KRAS, and allele-specific KRAS treatment approaches, a large body of preclinical/clinical data has quickly and comprehensively delineated a multitude of resistance mechanisms to first-generation “OFF-state” inhibitors such as sotorasib and adagrasib. Addressing acquired and adaptive resistance mechanisms will require perseverance and innovation with clinical trial combination approaches, while more preclinical focus is still necessary for understanding intrinsic resistance and resistance conferred by histological transformation. To help process this challenge, this chapter will highlight current disparities/mismatches that exist between clinical and preclinical approaches to RAS translation.",

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AB - The discovery and breakthrough of KRASG12C inhibitors have been described as “the end of the beginning” for RAS precision medicine. In parallel with development of a new generation of pan-RAS, pan-KRAS, and allele-specific KRAS treatment approaches, a large body of preclinical/clinical data has quickly and comprehensively delineated a multitude of resistance mechanisms to first-generation “OFF-state” inhibitors such as sotorasib and adagrasib. Addressing acquired and adaptive resistance mechanisms will require perseverance and innovation with clinical trial combination approaches, while more preclinical focus is still necessary for understanding intrinsic resistance and resistance conferred by histological transformation. To help process this challenge, this chapter will highlight current disparities/mismatches that exist between clinical and preclinical approaches to RAS translation.

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