Abstract
Hyperinsulinemia drives resistance to PI3Kα inhibitors in tumors.
Major finding: Hyperinsulinemia drives resistance to PI3Kα inhibitors in tumors.
Mechanism: Insulin feedback increases serum glucose and insulin levels to block the efficacy of PI3Kα inhibitors.
Impact: SGLT2 inhibition or a ketogenic diet may enhance the efficacy of PI3Kα inhibitors.
Oncogenic mutations in the enzyme phosphoinositide-3-kinase catalytic subunit alpha (p110α, encoded by PIK3CA), which mediates intracellular insulin responses, activate the PI3K–AKT–mTOR signaling axis; however, many patients with PIK3CA mutations exhibit intrinsic resistance to PI3K inhibitors (PI3Ki). Given that PI3K inhibition–induced hyperglycemia is ablated upon pancreas-driven insulin feedback, except in patients with insulin resistance, Hopkins and colleagues monitored the blood glucose and insulin levels of mice treated with several PI3Kis currently in human clinical trials to elucidate the mechanisms underlying PI3Ki-mediated hyperinsulinemia. p110α-targeting drugs caused elevated blood glucose and insulin levels, consistent with observations in human trials with the same drugs. Autochthonous Cre-activated mutant Kras;Trp53R172H/+ (KPC) mouse pancreatic tumors exhibited increased glucose uptake soon after p110α inhibitor treatment, and ex vivo treatment of KPC tumor cells with levels of insulin similar to those observed in the blood following the treatment of mice with the p110α inhibitor partially rescued PI3Ki-mediated repression of PI3K signaling. PI3Ki-induced hyperinsulinemia was dramatically suppressed when KPC allograft–bearing mice received a sodium–glucose co-transporter 2 inhibitor or were placed on a ketogenic diet prior to PI3Ki treatment, whereas mice treated with metformin prior to PI3Ki therapy did not exhibit this repression in PI3Ki-induced hyperinsulinemia. Further, PI3Ki treatment shrunk KPC tumors when hyperinsulinemia was suppressed but was ineffective as a monotherapy, and the combination of the ketogenic diet and PI3Ki therapy decreased growth of patient-derived endometrial tumor xenografts and extended survival in a mouse model of acute myeloid leukemia. Similarly, injection of insulin abrogated the antitumor efficacy of the combination of a PI3Ki and the ketogenic diet in mice harboring Pi3kca-mutant breast allografts. Inducible knockdown of the insulin receptor in KPC tumors resulted in decreased tumor growth in the presence, but not the absence, of PI3Ki. These results identify and characterize the mechanism underlying insulin feedback–mediated PI3Ki resistance and identify potential strategies to improve PI3K-targeted therapies.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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