RAS signaling in carcinogenesis, cancer therapy and resistance mechanisms
Xiaojuan Yang1, Hong Wu2,3
1Liver Digital Transformation Research Laboratory, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, P.R. China.
Abstract:
Variants in the RAS family (HRAS, NRAS and KRAS) are among the most common mutations found in cancer. About 19% patients with cancer harbor RAS mutations, which are typically associated with poor clinical outcomes. Over the past four decades, KRAS has long been considered an undruggable target due to the absence of suitable small-molecule binding sites within its mutant isoforms. However, recent advancements in drug design have made RAS-targeting therapies viable, particularly with the approval of direct KRASG12C inhibitors, such as sotorasib and adagrasib, for treating non-small cell lung cancer (NSCLC) with KRASG12C mutations. Other KRAS-mutant inhibitors targeting KRASG12D are currently being developed for use in the clinic, particularly for treating highly refractory malignancies like pancreatic cancer. Herein, we provide an overview of RAS signaling, further detailing the roles of the RAS signaling pathway in carcinogenesis. This includes a summary of RAS mutations in human cancers and an emphasis on therapeutic approaches, as well as de novo, acquired, and adaptive resistance in various malignancies.
Insights
RAS mutations are common in cancer and linked to poor outcomes. Recent therapies targeting KRAS, like KRASG12C inhibitors, offer new hope, with ongoing research for other RAS variants and resistance mechanisms.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- RAS family (HRAS, NRAS, KRAS) mutations are prevalent in approximately 19% of cancers, correlating with adverse clinical prognoses.
- Historically, KRAS was considered undruggable due to a lack of suitable binding sites in its mutant forms.
- The RAS signaling pathway plays a critical role in cellular signaling and is frequently dysregulated in various malignancies.
Purpose of the Study:
- To provide a comprehensive overview of RAS signaling pathways and their involvement in carcinogenesis.
- To summarize the landscape of RAS mutations across different human cancers.
- To highlight current and emerging therapeutic strategies targeting RAS mutations and address resistance mechanisms.
Main Methods:
- Literature review and synthesis of existing research on RAS signaling, mutations, and therapeutics.
- Analysis of clinical data regarding the prevalence and outcomes of RAS-mutated cancers.
- Examination of drug development pipelines for RAS-targeted therapies, including inhibitors for KRASG12C and KRASG12D.
Main Results:
- Recent advancements have led to the development of direct KRASG12C inhibitors (e.g., sotorasib, adagrasib) approved for non-small cell lung cancer (NSCLC).
- Targeted therapies for other RAS mutations, such as KRASG12D, are under development, particularly for pancreatic cancer.
- Understanding de novo, acquired, and adaptive resistance is crucial for optimizing long-term treatment efficacy.
Conclusions:
- Targeting RAS mutations, once deemed undruggable, is now a reality with approved therapies and promising drug candidates.
- Continued research into RAS signaling, mutation profiles, and resistance mechanisms is essential for advancing cancer treatment.
- The development of novel therapeutic strategies holds significant potential for improving outcomes in patients with RAS-mutated cancers.
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