Background
Sotorasib and adagrasib are two new compounds that can help us to understand the mechanisms of KRAS mutations. Mutated forms of the gene KRAS encourage cell proliferation and are involved in a large fraction of all cancers. Although this gene was discovered in the 1980s, scientists have long struggled to find chemotherapies that target it. That’s because of a lack of binding sites. The new drugs sotorasib and adagrasib can bind to and inhibit one kind of mutated KRAS. Sotorasib has been approved for the treatment of non-small-cell lung cancer and adagrasib is in clinical trials.
Non-small-cell lung cancer has a history of developing resistance to drug treatments. So, it’s likely that patients may suffer resistance when sotorasib and adagrasib enter clinical use. Recently, a team of cancer researchers sought to understand resistance to these new drugs, to improve strategies to prevent it.
Experimental
The researchers exposed a cell culture line of non-small-cell lung cancer to sotorasib or adagrasib, with added N-ethyl-N-nitrosurea to encourage mutations. Then they analyzed the KRAS mutations that resulted. Five of the mutations were resistant to one drug but not the other. Therefore, sequential treatment with these drugs might help patients with this kind of resistance. Two of the KRAS mutations that emerged were resistant to both drugs. A cocktail of BI-3406 and trametinib inhibits cells with this mutation, so this cocktail might help patients who have this kind of resistance.
The mutations found in this study are not exhaustive of all the KRAS mutations. Additional mutations may appear when patients are treated with these chemicals. However, this study made good progress toward understanding the mechanisms behind KRAS chemotherapy resistance.
Koga T, Suda K, Fujino T, et al. KRAS secondary mutations that confer acquired resistance to KRAS G12C inhibitors, sotorasib and adagrasib, and overcoming strategies: insights from in vitro experiments. Journal of Thoracic Oncology. 2021 Aug;16(8):1321-1332. PMID: 33971321. doi: 10.1016/j.jtho.2021.04.015