Recent studies have shown that compensatory signaling pathways, such as the PI3K/AKT/mTOR pathway, and epigenetic reprogramming, e.g., epithelial-to-mesenchymal transition (EMT), are common mechanisms that mediate intrinsic resistance to KRASG12C inhibitors, whereas acquired resistance and ensuing recurrent disease can arise when cancer cells acquire secondary mutations in the KRAS protein that impair the covalent binding of KRASG12C inhibitors. The gene discussed is AKT1; the disease is cancer.