Tumours with PI3K activation are resistant to dietary restriction

Dietary restriction (DR) delays the incidence and decreases the growth of various types of tumours, but the mechanisms underlying the sensitivity of tumours to food restriction remain unknown. We find that certain human cancer cell lines, when grown as tumour xenografts in mice, are highly sensitive to the anti-growth effects of DR, while others are resistant. Cancer cells that form DR-resistant tumours carry mutations that cause constitutive activation of the PI3K pathway and in culture proliferate in the absence of insulin or IGF1. Substitution of an activated mutant allele of PI3K with wild-type PI3K in otherwise isogenic cancer cells, or the restoration of PTEN expression in a PTEN-null cancer cell line, is sufficient to convert a DR-resistant tumour into one that is DR-sensitive. DR does not affect a PTEN-null mouse model of prostate cancer, but significantly decreases tumour burden in a mouse model of lung cancer lacking constitutive PI3K signaling. Thus, the PI3K pathway is a major determinant of the sensitivity of tumours to DR and activating mutations in the pathway may influence the response of cancers to DR-mimetic therapies.