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A RAS renaissance: emerging targeted therapies for KRAS-mutated non-small cell lung cancer
Neil Vasan1, Julie L Boyer2, Roy S Herbst3
1Department of Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts;
Abstract:
Of the numerous oncogenes implicated in human cancer, the most common and perhaps the most elusive to target pharmacologically is RAS. Since the discovery of RAS in the 1960s, numerous studies have elucidated the mechanism of activity, regulation, and intracellular trafficking of the RAS gene products, and of its regulatory pathways. These pathways yielded druggable targets, such as farnesyltransferase, during the 1980s to 1990s. Unfortunately, early clinical trials investigating farnesyltransferase inhibitors yielded disappointing results, and subsequent interest by pharmaceutical companies in targeting RAS waned. However, recent advances including the identification of novel regulatory enzymes (e.g., Rce1, Icmt, Pdeδ), siRNA-based synthetic lethality screens, and fragment-based small-molecule screens, have resulted in a "Ras renaissance," signified by new Ras and Ras pathway-targeted therapies that have led to new clinical trials of patients with Ras-driven cancers. This review gives an overview of KRas signaling pathways with an emphasis on novel targets and targeted therapies, using non-small cell lung cancer as a case example.
Insights
Targeting the common oncogene RAS in cancer has been challenging. Recent advances reveal novel targets and therapies for Ras-driven cancers, including non-small cell lung cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- RAS oncogenes are frequently implicated in human cancers.
- Targeting RAS has been historically difficult due to its complex mechanisms.
- Previous attempts with farnesyltransferase inhibitors showed limited success.
Purpose of the Study:
- To review KRas signaling pathways.
- To highlight novel targets and therapeutic strategies for Ras-driven cancers.
- To use non-small cell lung cancer as a specific case example.
Main Methods:
- Literature review of RAS gene products, regulatory pathways, and trafficking.
- Analysis of recent advances in identifying novel regulatory enzymes (Rce1, Icmt, Pdeδ).
- Examination of siRNA-based synthetic lethality screens and fragment-based small-molecule screens.
Main Results:
- Identification of novel druggable targets beyond farnesyltransferase.
- Development of new Ras and Ras pathway-targeted therapies.
- Initiation of new clinical trials for Ras-driven malignancies.
Conclusions:
- A resurgence in targeting RAS ('Ras renaissance') is underway.
- Novel enzymes and screening methods are driving progress in Ras-targeted therapy.
- Targeted therapies show promise for treating Ras-driven cancers like non-small cell lung cancer.
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