The development of KRAS selective inhibitors promises to expand treatment to a broader population of patients with KRAS-mutated tumours
Discovered almost 40 years ago, the KRAS oncogene has long been an elusive target for cancer treatment. Despite its status as the most frequently mutated oncogene in human cancer, it was considered undruggable with small molecule inhibitors until recently. However, the development of mutation-selective KRAS inhibitors has ushered in a new era in cancer therapy for patients with KRAS-mutant cancers. In gastrointestinal cancers, such as pancreatic and colorectal cancers, where KRAS mutations are particularly prevalent, these advancements hold transformative potential.
The initial breakthrough in targeting KRAS was achieved with the development of inhibitors that interact specifically with the KRAS G12C mutation. Successful clinical trials led to the regulatory approval of sotorasib and adagrasib for the treatment of non-small cell lung cancer. Both agents have since demonstrated antitumour activity in colorectal cancer, particularly when combined with an EGFR inhibitor to counteract resistance mechanisms (N Engl J Med. 2023;389:2125–2139; N Engl J Med. 2022;388:44–54), and in pancreatic cancer (N Engl J Med. 2023;388:33–43; J Clin Oncol. 2023;41:4097–4106). Insights gained from G12C inhibitors have paved the way for developing mutation-selective inhibitors for more common KRAS mutations, including G12D found in up to 25% of all KRAS-mutated cancers. These inhibitors are currently entering early clinical development with high hopes for success.
Targeting the broader range of KRAS mutations beyond the most common ones presents challenges due to the impracticality of developing specific inhibitors for each mutation. This has led to the development of pan-RAS inhibitors, which target all KRAS mutations as well as wild-type KRAS and the other RAS isoforms, NRAS and HRAS. While this broad approach has the potential to benefit the large population of patients whose tumours are driven by less common KRAS mutations, it also poses a risk of toxicity to healthy cells. Nevertheless, early clinical experience indicates promising antitumour activity with manageable tolerability (Ann Oncol. 2023;34(Suppl_2):S458). In addition, recent animal studies suggest that tumour cells may be more sensitive to pan-RAS inhibitors than normal tissues (Nature. 2024;629:927–936).
The latest advancement in KRAS inhibition is the development of KRAS selective inhibitors. These agents inhibit all KRAS mutations while sparing NRAS and HRAS (Nature. 2023;619:160–166). This selectivity allows normal cellular functions mediated by NRAS and HRAS to continue while effectively targeting the mutated KRAS. If successful, these inhibitors could target over 95% of KRAS mutations, offering a comprehensive treatment option for a broad patient population.
The development of these three classes of KRAS inhibitors has the potential to transform how we treat diseases such as pancreatic and colorectal cancer. Looking to the future, it will be critical to establish the tolerability of KRAS-selective inhibitors in humans. In addition, we need to expand our understanding of why treatment resistance to KRAS inhibitors occurs and develop strategies that produce durable treatment responses. Combining KRAS inhibitors with other therapeutic modalities, such as immunotherapies, may enhance their efficacy and lead to more sustained remissions.
