Emerging landscape of KRAS inhibitors in cancer treatment

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• RAS pathway alterations (KRAS, NRAS, HRAS) are prevalent in approximately 20% of cancers.
• Mutant-selective KRAS G12C inhibitors represent a breakthrough in targeting oncogenic RAS.
• Resistance to first-generation KRAS G12C inhibitors necessitates the development of novel therapeutic strategies.

Purpose of the Study:

• To review the clinical evidence of KRAS G12C inhibitors across various cancer types.
• To identify and discuss key mechanisms of acquired resistance to KRAS G12C inhibitors.
• To explore the landscape of next-generation (K)RAS inhibitors, including their mechanisms, selectivity, and clinical potential.

Main Methods:

• Literature review of clinical trials and preclinical studies on KRAS inhibitors.
• Analysis of resistance mechanisms reported in clinical and experimental settings.
• Comparative assessment of novel (K)RAS inhibitor classes based on target coverage and mechanism of action.

Main Results:

• First-generation KRAS G12C inhibitors demonstrate proof-of-concept but face significant resistance challenges.
• Multiple resistance mechanisms, including secondary RAS mutations and pathway reactivation, limit durable responses.
• Next-generation inhibitors exhibit diverse mechanisms and broader target profiles, showing promise in preclinical and early clinical studies.

Conclusions:

• Overcoming resistance is critical for maximizing the benefit of RAS-targeted therapies.
• Novel (K)RAS inhibitors offer potential to circumvent resistance and expand treatment options for a wider patient population.
• Further clinical investigation is required to establish the efficacy and safety of emerging RAS-targeted therapies.