Pharmacological targeting of SOS1-RAS interaction triggers pancreatic β-cell proliferation and sustainably reverses diabetic hyperglycemia
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Clinical studies have suggested that restoring a sufficient mass of functional β cells can provide an effective treatment option for diabetes, however, it remains unclear whether this can be achieved through pharmacological stimulation of endogenous β-cell proliferation. We demonstrate here that ectopic expression of a constitutively active form of Kras (KrasG12D) exclusively in pancreatic endocrine cells suppresses β-cell proliferation, resulting in a dramatic reduction in β-cell numbers and islet size. Conversely, we demonstrate that the potent and selective SOS1-RAS interaction inhibitor BI-3406 promotes unprecedented levels of β-cell proliferation in primary human islets, both in culture and following transplantation in immunocompromised diabetic mice. Importantly, using murine models of streptozotocin-induced diabetes, we show that BI-3406 treatment restores β-cell mass, leading to a gradual normalization of blood glucose and insulin levels, as well as to sustainable improvement in glucose tolerance. Our data provide the first pre-clinical evidence of an orally bioavailable KRAS inhibitor that can directly induce β-cell regeneration.
