Endocrine Abstracts

Background: Neuroendocrine tumors (NETs) are slow growing tumors whose incidence has risen precipitously compared to all other malignancies. These tumors develop via transformation of neuroendocrine cells throughout the body; however, they are predominantly found in the pancreas, lungs, and intestines. NETs are extremely slow-growing tumors that respond poorly to traditional anti-cancer therapies, and unfortunately patients with unresectable or partially resectable tumors will inevitably progress on the currently approved therapies. Therefore, there is a critical need to identify new drugs and/or combination therapies for treating resistant tumors. Our group has shown that pancreatic NETs (pNETs) overexpress an oncogenic Rab-like GTPase, RABL6A. RABL6A upregulates many kinases, such as CDK4/6, MEK, and AKT whose hyperactivation is a key feature of pNET and lung NET pathogenesis. Monotherapies targeting these kinases individually have not been effective when tested in pNET patients. We hypothesized that combination therapy targeting both CDK4/6 and MEK together would have synergistic antitumor activity against pNETs and lung NETs.

Methods: Anti-tumor effects of the drugs – vehicle control, CDK4/6 inhibitor (palbociclib), MEK inhibitor (mirdametinib), or the combination – were measured in vitro in cultured pNET and lung NET cells via cell cycle, cell survival, and drug synergy assays. Western blotting of phosphorylated RB1 protein evaluated activity of the drugs against their target. The in vivo activity of the drugs, alone or combined, was measured in xenograft tumors of each NET type (BON1 and H727) in immune-deficient NSG mice.

Results: Dual CDK4/6-MEK inhibitor therapy was highly synergistic in vitro where it caused robust pNET cell cycle arrest and cell death relative to single drug controls. The combination was also synergistic at nanomolar doses against a lung NET cell line, H727. Importantly, molecular assays showed the CDK4/6-MEK inhibitor combination effectively inactivated the targeted pathway, as measured by RB1 protein hypo-phosphorylation. In animals bearing pNET xenografts, the CDK4/6-MEK inhibitor combination significantly slowed tumor growth and yielded a 6-fold extension in average mouse survival (~120 days vs 20 days for vehicle control). Pilot drug studies of H727 lung NET xenografts showed significant anti-tumor activity of MEK inhibition alone.

Conclusions: Combination therapy targeting CDK4/6 and MEK kinases effectively inhibits NET growth in vitro and in vivo, suggesting it could be a valuable treatment option for NET patients. To date, most analyses have been conducted in pNET models; therefore, future studies will be expanded to more deeply examine the anti-tumor activities of CDK4/6 and MEK inhibitors in lung NET models.

ABSTRACT ID28786