Abstract 1742: Cediranib reverses taxane resistance in CLIP-170S expressing gastric cancer

Abstract

Abstract Taxane-based chemotherapy is a first-line treatment for patients with Gastric Cancer (GC), however, many will not respond due to mechanisms of resistance. Recently, we reported the discovery of a novel truncated variant of the microtubule plus-end binding protein CLIP-170, hereafter CLIP-170S, whose expression is enriched in taxane-resistant cell lines and in 65% of patients with GC, non-responsive to Cabazitaxel monotherapy. CLIP-170S knockdown reversed taxane resistance and its ectopic expression led to resistance, suggesting causation. Computational analysis of RNA-seq data in conjunction with the connectivity map from taxane-sensitive and -resistant GC cell lines, predicted imatinib as the top candidate drug to overcome drug resistance. Imatinib treatment completely reversed taxane resistance, experimentally confirming the prediction, and did so unexpectedly by selective depletion of CLIP-170S. Other RTK inhibitors, such as Sunitinib, Ponatinib, Axitinib, and Cediranib also depleted CLIP-170S, suggesting a class effect, however, the mechanism is unknown. To investigate the mechanism of RTKi induced depletion of CLIP-170S, we sought to investigate the involvement of proteasomal and lysosomal cellular compartments. Preliminary results indicated that treatment of CLIP-170S expressing cells with Imatinib or Cediranib led to an increase in lysosome size, suggesting increased lysosomal activity. In parallel, we are testing in-vivo the synergistic activity of the RTKi, Cediranib, in combination with docetaxel in GC tumors expressing CLIP-170S. Together, these results will allow us to implement a novel clinical trial for patients with GC by using Cediranib as a treatment to increase taxane efficacy through CLIP-170S depletion. Citation Format: William G. Stone, Urko del Castillo, Prashant V. Thakkar, Manish A. Shah, Paraskevi Giannakakou. Cediranib reverses taxane resistance in CLIP-170S expressing gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1742.