{'fraction_non_alphanumeric': 0.022917831190609278, 'fraction_numerical': 0.013974287311347122, 'mean_word_length': 5.4855072463768115, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Recent developments, challenges and opportunities in targeting the KRAS pathway



KRAS is a highly mutated gene among cancers, especially in lung, pancreatic and colorectal cancers (CRC). Despite extensive efforts in the past three decades, KRAS remains undruggable. But lately, inhibitors selectively binding to cysteine mutant at 12th position (G12C) are in clinical trials as a single agent and combination with other drugs. FDA approved LUMAKRAS (Sotorasib, AMG510) for metastatic NSCLC, while Adagrasib (MRTX849) is under clinical trials and it is showing good safety and efficacy in pancreatic and GI tumors. Both these molecules demonstrated better response in NSCLC but have less efficacy in colorectal and other solid cancers. Among non G12C KRAS mutant cancers, promising data is emerging from G12D inhibition. This review covers the status of KRAS G12C, non G12C inhibitors and discusses different nodal proteins in RAS signaling pathway, mechanism of resistance in targeted therapy and combination approaches. Ongoing clinical trials with G12C inhibitors have promising results. However, a combination of KRAS inhibition with other inhibitors of signaling components in vertical axis (SHP2, SOS1, MEK, PI3K/AKT and EGFR inhibitors) might be beneficial for durable clinical response. Sotorasib in combination with MEK inhibitor showed promising results in preclinical xenograft and PDx models of KRAS mutated cancers. Although at a preclinical stage, other approaches like Tri complex inhibitor, KRAS (ON) inhibitors and non G12C inhibitors are of significant interest in KRAS drug discovery. Multiple targeted approaches are being explored based on tumor specific gene expression profiles considering dynamic nature of KRAS activity and heterogeneity of hard to treat tumors.
