Oncogenic mutation in KRAS is one of the most common alterations in human cancer. After decades of extensive research and unsuccessful drug discovery programs, therapeutic targeting of KRAS mutant tumour is at an exciting juncture. The discovery of mutation-specific inhibitors of KRASG12C and early positive findings from clinical trials has raised the hope of finally having a drug to treat a significant segment of KRAS mutant cancer patients. Crucially, it has also re-energized the RAS field to look beyond G12C mutation and find new innovative targeting opportunities. However, the early clinical trial data also indicates that there is significant variation in response among patients and that monotherapy treatment with KRASG12C inhibitors (G12Ci) alone is unlikely to be sufficient to elicit a sustained response. Understanding the molecular mechanism of variation in patient response and identifying possible combination opportunities, which could be exploited to achieve durable and significant responses and delay emergence of resistance, is central to the success of G12Ci therapy. Given the specificity of G12Ci, toxicity is expected to be minimal. Therefore, it might be possible to combine G12Ci with other targeted agents which have previously been explored to tackle KRAS mutant cancer but deemed too toxic, e.g. MEK inhibitor. Ongoing clinical trials will shed light on clinical resistance to G12C inhibitors, however extensive work is already ongoing to identify the best combination partners. This review provides an update on combination opportunities which could be explored to maximize the benefit of this new exciting drug.

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