Targeting the glucagon receptor signaling pathway as a novel strategy to counteract PI3K inhibitor induced hyperglycemia while sustaining tumor PI3K inhibition

Pathologic activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is an oncogenic driver for many malignancies, including lymphomas [1]. Although validated as a therapeutic oncologic target, the PI3K signaling pathway is also implicated in normal glucose homeostasis. Specifically, since the PI3K subunit p110a is chiefly responsible for downstream insulin receptor (INSR) signaling, PI3K signaling inhibition that includes p110a leads to severe hyperglycemia. Both compensatory endogenous insulin release as well as treatment of hyperglycemia with exogenous insulin/insulin mimetics activate INSR-associated PI3K signaling, ultimately limiting blockade of tumor-associated PI3K signaling [2]. While aggressive lymphomas driven by pathologic PI3K signaling respond to combined PI3Ka and d/c inhibition, the antitumor effect is likely submaximal due to endogenous insulin feedback with subsequent PI3K activation, and more intense dosing of PI3K inhibitors is difficult to achieve safely due to severe hyperglycemia [3]. Attempts to control PI3Ka-associated hyperglycemia have included diet, metformin, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and insulin [4]. Insulin is problematic as it drives PI3K signaling that supports cancer growth [2]. Even endogenous insulin secretion, either occurring as feedback to PI3K induced hyperglycemia or as response to anti-hyperglycemic treatment with ‘secretagogues’, would counteract the anti-cancer effect of PI3K inhibition [2]. Hypoglycemic agents that would not be predicted to activate the PI3K pathway include metformin and SGLT2 inhibitors as they do not stimulate insulin production. Disappointingly, when metformin was given to mice prior to the administration of PI3K inhibitor, it had minimal impact on PI3K induced hyperglycemia and hyperinsulinemia. SGLT2 inhibition successfully suppressed both the insulin feedback and PI3K reactivation, but SGLT2 inhibition is not without drawbacks as SGLT2 inhibitors, which increase lipolysis and contribute to dehydration, have been reported to cause euglycemic diabetic ketoacidosis (DKA) [2,5]. This has specifically occurred in a non-diabetic patient with metastatic breast cancer with hyperglycemia on a PI3K inhibitor [6]. Finally, the ketogenic diet may be successful in curbing PI3K induced hyperglycemia and hyperinsulinemia, but this is difficult to apply in practice for most patients. Therefore, a novel strategy to maintain the blockade of tumor-associated PI3K signaling while reducing hyperglycemia is needed. Euglycemia is normally achieved by a balance of both insulin and its opposing hormone, glucagon. Insulin is secreted during the ‘fed state’ in order to enable glucose utilization, whereas glucagon is secreted during the ‘fasting state’, promoting hepatic glycogenolysis and gluconeogenesis. In insulin deficiency, insulin resistance, or lack of insulin receptor signaling as in PI3Ka blockade, there is overall glucose underutilization similar to ‘fasting’ states, and plasma glucagon levels are elevated. In this setting of hyperglycemia, paradoxically high glucagon levels would be expected to promote hepatic glucose output, further worsening hyperglycemia [7,8]. This unhelpful feed-forward cycle is present in all types of diabetes, and glucagon is now recognized as a key pathogenic factor [9]. Remarkably, glucagon receptor-deficient mice that have undergone beta islet cell destruction do not develop diabetes unless glucagon receptor function is restored [10,11]. It follows then that abrogating glucagon receptor (GCGR) signaling using an inhibitory monoclonal antibody to the glucagon receptor should ameliorate glycemic control in diabetes. This has been