Manipulation of the retinoic acid axis to circumvent cisplatin resistance in NSCLC

Title: Manipulation of the retinoic acid axis to circumvent cisplatin resistance in NSCLC
Author(s): L MacDonagh C Mulvey S Toland S Gray E Breen S Finn S Cuffe K O'Byrne M Barr
Institution: Thoracic Oncology Research Group, Trinity Translational Medicine Institute, Trinity College Dublin, School of Clinical Medicine, St. James's Hospital, Dublin 8
Poster: Click to view poster
Category: Lung Cancer/CF/ILD/Surgery
Abstract: Pan-resistance to platinum agents remains a major clinical challenge in NSCLC. Due to the lengthy process of drug design and trial attention has turned to the repurposing of approved drugs within therapeutic resistance. Cancer stem cells (CSCs) have been hypothesised to be the initiating cells of resistance. All-trans retinoic acid (ATRA) is a well-established chemotherapeutic agent in the treatment of acute promyelocytic leukaemia; it induces terminal differentiation of immature cells. We hypothesise that exploitation of the retinoic acid pathway will deplete the CSC population thereby restoring cisplatin sensitivity.
The presence of an ALDH1-positive CSC subpopulation within cisplatin resistant (CisR) sublines was confirmed by flow cytometry. Cells were treated with retinol or ATRA and the presence of CSCs reassessed. The functional parameters of proliferation, clonogenic survival and apoptosis were also assessed.
Retinol and ATRA significantly depleted CSCs. Retinol and ATRA used in combination with cisplatin significantly reduced proliferation and survival of CisR sublines while increasing apoptosis compared to cisplatin alone.
Exploitation of the vitamin A/retinoic acid pathway re-sensitised sublines to the cytotoxic effects of cisplatin. These data suggest vitamin A supplementation or the addition of FDA-approved ATRA to cisplatin-based regimens may be of clinical benefit in overcoming recurrence and cisplatin resistance.