Inhibition of PI3K by copanlisib exerts potent antitumor effects on Merkel cell carcinoma cell lines and mouse xenografts

Bin Fang,Haibo Zhao,Stephanie Zhao,Maki Yamamoto,Aarthi Kannan,Ling Gao,Samuel Ejadi,Quy H Nguyen,J Camilo Barreto

doi:10.1038/s41598-020-65637-2

Abstract

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer with steadily increasing incidence and poor prognosis. Despite recent success with immunotherapy, 50% of patients still succumb to their diseases. To date, there is no Food and Drug Administration-approved targeted therapy for advanced MCC. Aberrant activation of phosphatidylinositide-3-kinase (PI3K)/AKT/mTOR pathway is frequently detected in MCC, making it an attractive therapeutic target. We previously found PI3K pathway activation in human MCC cell lines and tumors and demonstrated complete clinical response in a Stage IV MCC patient treated with PI3K inhibitor idelalisib. Here, we found that both PI3K-α and -δ isoforms are abundantly expressed in our MCC cell lines and clinical samples; we therefore examined antitumor efficacy across a panel of five PI3K inhibitors with distinctive isoform-specificities, including idelalisib (PI3K-δ), copanlisib (PI3K-α/δ), duvelisib (PI3K-γ/δ), alpelisib (PI3K-α), and AZD8186 (PI3K-β/δ). Of these, copanlisib exerts the most potent antitumor effects, markedly inhibiting cell proliferation, survival, and tumor growth by suppressing PI3K/mTOR/Akt activities in mouse models generated from MCC cell xenografts and patient-derived tumor xenografts. These results provide compelling preclinical evidence for application of copanlisib in advanced MCC with aberrant PI3K activation for which immunotherapy is insufficient, or patients who are unsuitable for immunotherapy.

Highlights

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine malignancy of the skin with steadily increasing incidence[1,2,3]
We and others have previously demonstrated that the PI3K/mTOR/Akt pathway is commonly activated in MCC tumors[27,28,49,58]
Data from triplicate runs presented as mean ± SD. (B) Expression of PI3K-α and PI3K-δ in 50 archived human MCC tumor samples detected by immunohistochemistry

Summary

Introduction

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine malignancy of the skin with steadily increasing incidence[1,2,3]. Recent immunotherapy targeting the PD1/PD-L1 (programmed cell death protein 1/PD1 ligand) immune checkpoint pathway has demonstrated durable response rates and clinical benefits[11,12,13], indicating that tumoral immune cell infiltration and function play an important role in MCC development, growth, and clinical outcomes[14,15,16] Both pembrolizumab (humanized anti-PD-1 antibody) and avelumab (humanized anti-PD-L1 antibody) have been approved by the Food and Drug Administration (FDA) for treatment of advanced MCC17,18. PI3K/AKT/mTOR pathway regulates many cellular processes that are involved in carcinogenesis including cell cycle/proliferation, differentiation, survival, motility, and metabolism[30,31,32] This pathway is one of the most overactive pathways in a broad spectrum of solid tumors and hematological malignancies, making PI3K pathway an attractive therapeutic target for cancer treatment. We have demonstrated that MLN0128, a second generation dual TORC1/2 inhibitor, significantly attenuated MCC tumor growth in MCC cell line-derived (CDX) mouse models[49], confirming that this pathway is a valid therapeutic target in MCC

Methods

Results

Conclusion