KRAS is one of the most frequently mutated oncogenes in cancer.¹ Codon 12, 13 and 61 mutations are frequently observed as the hot spot mutations in various cancers. Normally, KRAS protein functions as a molecular switch downstream of cell surface receptors, such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor, etc., shuttling GTP-bound active state and GDP-bound inactive state, which turns on and off the growth factors’ signals that activate MAPK, PI3K/AKT/mTOR and other signalling pathways fundamental for cell proliferation, differentiation and survival. The oncogenic mutations lock the KRAS at the active state, resulting in contributing to tumorigenesis. Genetically engineered mouse models containing tissue-specific Kras codon 12 mutation have developed clinically relevant cancers in the corresponding tissues, which indicates the central driver role of KRAS mutation in cancer formation and progression.2

Therefore, targeting the mutated KRAS is considered an ideal therapeutic strategy in the KRAS-mutated cancers. Especially, KRAS codon 12 mutation is detected in 90% of pancreatic cancer,1 which suggests the tumour addiction to the mutated KRAS in the most deadly cancer with a 5-year survival of still around 10%. However, KRAS has been undruggable for more than 40 years, because of its relatively smooth protein structure and lack of approachable binding pocket.1

Recently, KRAS G12C-specific covalent inhibitors, sotorasib and adagrasib, that lock KRAS to a GDP-bound inactive state, were developed and clinically approved for the treatment of cancers with KRAS G12C mutation,3^,4 with significant therapeutic efficacy, especially in non-small cell lung cancer (NSCLC). It was a breakthrough in the field: Now, KRAS is druggable. Following them, other KRAS G12C inhibitors, as well as inhibitors specific for other KRAS mutations, have been on the line of development with growing expectations in the improvement of clinical practice.

Subsequent to the success of the KRAS G12C inhibitor, acquired resistance to the inhibitor has become a clinical problem and the underlying mechanisms have been explored.5 Compared to NSCLC, colorectal cancer with KRAS G12C mutation showed a limited objective response to the KRAS G12C inhibitors, indicating resistance to the therapy. To overcome the resistance, combinatorial therapeutics have been investigated with the KRAS G12C inhibitors. Recently, a couple of studies demonstrated the feasibility and possible efficacy of the combination of the KRAS G12C inhibitors with EGFR inhibitors in advanced colorectal cancer.6^-8 Among them, the CodeBreaK 300, a phase 3, multicenter, open-label, randomized trial (NCT05198934) showed that a KRAS G12C-specific inhibitor sotorasib, in combination with EGFR inhibitor panitumumab, was superior to the standard treatment in progression-free survival of the patients with chemorefractory metastatic colorectal cancer, with permissible toxic effects.6 These studies elucidated that the combinatorial inhibition of KRAS G12C and EGFR is a great strategy to overcome resistance in colorectal cancer. In line with this, another phase 3 randomized trial of adagrasib plus cetuximab, another combination of KRAS G12C inhibitor and EGFR inhibitor, is also ongoing in comparison with the standard chemotherapy in colorectal cancer with KRAS G12C mutation (KRYSTAL-10, NCT04793958).

However, unfortunately, KRAS G12C mutation is rarely detected in pancreatic cancer (1%–2%), thus, its clinical impact on pancreatic cancer is limited. In contrast, KRAS G12D is detected in 43% of pancreatic cancer patients, which is the most frequent mutation pattern, therefore, clinical approval of KRAS G12D inhibitor for pancreatic cancer is promisingly awaited. In preclinical studies, its significant impact on controlling pancreatic cancer with KRAS G12D mutation has already been confirmed,9 indicating that it can be a striking game changer in the clinical practice of pancreatic cancer. The underlying mechanisms of resistance to the KRAS G12D inhibitor should also be considered and conquered. The combinatorial strategy with EGFR inhibitor provides insight into it.

Of note, the trials of KRAS G12C inhibitors described above as well as most of the ongoing trials with KRAS-specific inhibitors were designed for the second-line treatment setting or later, in which the previous treatment(s) should have affected the patients’ performance and the acquired chemoresistance. It is not hard to imagine that any treatment can drive resistance acquisition in cancer to a greater or lesser extent, thus the EGFR signal activation might have been caused by the previous treatment(s). Considering that KRAS mutation is a central driver of cancer formation and progression, it might be worth investigating the efficacy of mutant KRAS-specific inhibitors in the first-line treatment setting: direct targeting the driver mutation of KRAS can be more effective for the treatment-naïve cancer patients than the patients after receiving certain treatment(s). Currently, a couple of phase 3 trials using KRAS G12C inhibitor are ongoing to be approved as the first-line therapy, in addition, several phase 2 studies are also designed for the first-line or neoadjuvant setting (Table 1). The outcomes are highly anticipated, but all of them are designed only for NSCLC and there are no such trials for colorectal cancer or pancreatic cancer yet.

Meanwhile, it might also be desirable that clinical trials of KRAS G12D inhibitor, which are still in an early phase, are evaluated in the first-line setting at phase 2/3 without delay. According to the preclinical therapeutic impact of the KRAS-specific G12D inhibitor,9 we can expect a significant improvement in the prognosis of cancer with KRAS G12D mutation: the objective response to the first-line KRAS G12D inhibitor might increase the resectability in the conversion surgery in the advanced cancer patients, especially in pancreatic cancer, most of the patients are currently unresectable state. Clinical trials take time in general, especially large-scale phase 3 trials for the clinical approval of novel therapies, whereas a number of advanced cancer patients have been waiting for highly effective therapies with hope. Hence it is extremely important that novel effective therapies are approved to be available as soon as possible through the clinical trials. The first-line treatment with KRAS-specific inhibitors (in combination with EGFR inhibitors, etc.) will significantly benefit KRAS-mutated cancer patients with currently dismal prognoses.

AUTHOR CONTRIBUTIONS

Hideaki Ijichi designed and wrote this manuscript.

CONFLICT OF INTEREST STATEMENT

The author declares no conflict of interest.

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This manuscript is not supported by specific funding.

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