90 Recent advancements in the development of KRAS inhibitors have brought renewed hope for patients suffering from various types of cancer. KRAS mutations, particularly the p.Gly12Cys (G12C) variant, have long been considered undruggable due to the structural characteristics of the KRAS protein. But, big steps forward in bioengineering and medicinal chemistry have made it possible to create and get approval for two strong KRAS G12C inhibitors: sotorasib and adagrasib. These agents have demonstrated significant antitumour activity in highly refractory malignancies such as non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC). The findings were published in the journal Nature Medicine. KRAS, a member of the RAS family, is a critical protein involved in cell signalling pathways that regulate growth and proliferation. Mutations in KRAS, particularly those that keep the protein in an active ‘on’ state, drive oncogenesis in approximately 20% of all human cancers. In the past, it has been hard to make KRAS inhibitors because the protein has a strong affinity for GTP, there are not any deep binding pockets, and the protein’s conformational states need to be changed selectively. These hurdles rendered the KRAS protein undruggable for nearly four decades. The first significant breakthrough came with the development of allele-specific inhibitors targeting the KRAS G12C mutation. Sotorasib and adagrasib, both G12C inhibitors, have shown promising results in clinical trials. Sotorasib, for instance, has demonstrated a 28.1% objective response rate (ORR) in NSCLC patients, with a median progression-free survival (PFS) of 5.6 months. Similarly, adagrasib has shown a 42.9% ORR and a median PFS of 6.5 months in the same patient population. These results mark a significant milestone in the fight against KRAS-mutant cancers, providing effective treatment options where previously there were none. Recent research efforts have focused on expanding the efficacy of KRAS inhibitors beyond the G12C mutation. As a tri-complex inhibitor that targets multiple RAS isoforms, RMC-6236 has shown strong preclinical activity against a number of RAS genotypes. Early clinical data from patients with NSCLC and PDAC have reported encouraging results, with ORRs of 38% and 20%, respectively. This agent’s ability to target multiple RAS mutations suggests a broader applicability in treating various cancer types. BI-2865 is another promising candidate, designed to inhibit multiple KRAS mutations, including G12D, G12V, G12C, and G13D, while sparing other RAS family proteins. This selective inhibition method aims to keep the drug’s effectiveness while minimising its side effects. This could make BI-2865 a useful addition to the fight against KRAS-mutant cancers. The emergence of resistance to KRAS inhibitors, both primary and acquired, remains a significant challenge. Many times, tumours get new mutations that turn on the RAS-MAPK signalling pathways again. This makes KRAS-targeted therapies less effective. To address this, researchers are exploring combination therapies that target multiple points along the signalling pathways. In preclinical and early clinical studies, it has been shown that using KRAS inhibitors with drugs that target RTKs, downstream effectors, or parallel pathways can be helpful. For instance, combining sotorasib with the EGFR inhibitor panitumumab in colorectal cancer (CRC) patients has improved clinical outcomes. The phase 3 CodeBreaK 300 trial demonstrated an ORR of 26.4% and a median PFS of 5.6 months for this combination, compared to an ORR of 0% and a median PFS of 2.2 months for standard care. The field of KRAS therapeutics is rapidly evolving, with numerous novel inhibitors and combination strategies under investigation. Tri-complex inhibitors, PROTAC degraders, and pan-RAS inhibitors represent the next wave of innovation. These methods try to get around the problems with allele-specific inhibitors by working better with more KRAS mutations and making resistance less likely.