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Phosphatidylinositol 3-kinase inhibitor enhances anti-tumour efficacy in paclitaxel-resistant cervical cancer

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ESGO State of the Art 2018 Conference

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Abstract

Instruction Cervical cancer is the third most common gynecological malignancy and responsible for 10-15% of cancer-related death in women. Conventional treatment options (e.g., chemotherapy, radiation and surgical resection) are known to be ineffective to most of the patients with advanced or recurrent cervical cancer and it is necessary to find optimal treatment agents. Paclitaxel is a front-line chemotherapeutic agent for cervical cancer (used alone or in combination with other therapeutic agent) with the response rate of 29-63% but chemo-resistance may occur, leading to dismal prognosis PI3K pathway is considered to play an important role in tumorigenesis and its inhibition may lead to immune-modulatory effect. Genomic landscape of cervical cancer has been elucidated and ~15% of cervical cancers harbor PIK3CA mutations  and other PI3K pathway-related genetic alterations. Therefore, targeted agents that inhibit the PI3K-AKT-mTOR pathway have been developed to be used in cervical cancer. Previous study showed that combination of paclitaxel and PI3K pathway-inhibitor down-regulate the PI3K activity more than either agent alone. However, whether the combinatory therapy would have immune-modulatory effect has not been elucidated. Objective We attempted to investigate whether Phosphatidylinositol 3-kinase (PI3K) pathway-inhibitor would be effective in paclitaxel-resistance cervical cancer. Materials and Methods Naive and palitaxel-resistant ME180 human cervical tumor cells were used and a PI3K inhibitor (Alpelisib; BYL719) was treated. Proteom profiler antibody arrays (Proteom Profiler Human XL Oncology Array, R&D SYSTEMS, USA) and western blot analysis were performed. Results HIF-1a, PDGF-AA, VEGF, MMP2 and VE-cadherin were overexpressed in paclitaxel-resistant ME180 cervical cancer cell line when compared to the naive one. However, after treating the PI3K inhibitor (Alpelisib; BYL719) the overexpressed proteins recovered. Conclusion Paclitaxel-resistance is known to be related to hypoxia but not many study was investigated to overcome the resistance. We suggest that PI3K inhibitor may enhance antitumor activity in cervical cancer through cascade of signalign events including HIF-1a and VEGF.

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© Copyright 2020 Morressier GmbH.
All rights reserved.