The Retinoblastoma Tumor Microenvironment Contributes to Drug Resistance

Abstract

Purpose : Purpose: Vitreous seeding remains the greatest challenge in treating retinoblastoma (Rb) in part due to their unique location and resistance to current therapies. Previously, we demonstrated the presence of members of the ATP-binding cassette (ABC) transporter family in Rb. These proteins are involved in drug efflux of both carboplatin and melphalan and may warrant therapeutic value to reduce vitreous seed drug resistance.

Methods : Methods: Using RNA isolated from nine naïve Rb patients with vitreous seeding, we quantified levels of primary ABC transporters (ABCB1, ABCC1, ABCC2, and ABCG2) and CD44 and compared to 5 healthy human vitreous controls by qPCR. We measured ABC transporter function through use of a cell-permeable fluorescent dye by flow cytometry. We also examined the percentage of Y79 Rb cells expressing CD44 by flow cytometry. Furthering our previous studies on PDGF-PDGFRb signaling, we investigated the role of this pathway in Rb drug resistance.

Results : Results: We measured high mRNA expression of all ABC transporters as well as CD44 in Rb patients relative to healthy vitreous. We also demonstrated an abundance of CD44⁺ Y79 Rb cells, which was reduced after disruption of PDGF-PDGFRb signaling.

Conclusions : Conclusion: In this study we demonstrate expression of key players implicated in drug resistance in the vitreous of Rb patients. Furthermore, as previous work from our group has shown the importance of PDGF-PDGFRb signaling in Rb cell survival, we demonstrated how disruption of this signaling cascade may aid in reducing drug resistance of Rb cells

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.