Fasting-mimicking diet potentiates anti-tumor effects of CDK4/6 inhibitors against breast cancer by suppressing NRAS- and IGF1-mediated mTORC1 signaling.

Fasting-mimicking diet (FMD) cycles, defined as 3-5 day periods of a calorie-restricted, low-protein, low-carbohydrate, and high-fat diet, have emerged as a dietary approach to delay cancer initiation and progression in both autograft and xenograft mouse models and as a safe and feasible approach to decrease risk factors for cancer and other age-related pathologies in humans. A substantial number of pre-clinical studies focused on various tumor types have shown that fasting/FMDs can potentiate the efficacy of various standard-of-care cancer therapies but also modulate the immune system to promote a T cell-dependent attack of tumor cells. Importantly, combining drug treatment with fasting/FMDs can overcome acquired drug resistance which frequently emerges and reduces long-term treatment benefits. However, the mechanisms by which the FMD reverts resistance to CDK4/6i remain poorly understood. Here, Li and colleagues provide evidence that FMD cycles act as a wild card to reduce the activity of a signaling network that includes IGF-1, RAS, AKT, and mTOR-S6K to delay cancer progression and reverse the acquisition of drug resistance. These findings expand the mechanistic understanding of the FMD-mediated increase in drug efficacy and provide further evidence to support trials combining hormone therapy, CDK4/6 inhibitors, and FMD in breast cancer treatment. These new results on FMD cycles add an optimistic outlook to extend the efficacy of standard-of-care drugs that eventually become ineffective because of acquired resistance.