Abstract 78P
Background
Gastrointestinal Stromal Tumors (GIST) is the most common malignant mesenchymal neoplasm. These tumors originate from oncogenic gain-of-function mutations in receptor tyrosine kinase genes, mainly in KIT and PDGFRA. Current treatments are based on tyrosine kinase inhibitors against these receptors, such as first-line Imatinib (IM). However, patients develop resistance to IM, leading to a dismal prognosis. This highlights the critical need to unravel the molecular mechanisms behind this resistance to develop novel approaches. In this context, we aimed to interrogate the role of the YAP1/TAZ pathway in GIST, based on prior works from our group that evidenced its implication in smooth muscle cell plasticity (Guérin et al. 2020) and IM resistance (Ruiz-Demoulin et al. 2023).
Methods
We aimed to individually silence YAP1 or TAZ proteins using RNAi technology with the long-term objective of developing a novel therapeutic approach. Thus, siRNAs specifically targeting YAP1 or TAZ were designed, encapsulated in our WRAP (W- and R-rich peptide)-based nanoparticles, and applied to GIST cells.
Results
showed that siRNA-loaded nanoparticles were easily delivered in GIST cells in less than one hour. More importantly, both protein levels (YAP1 or TAZ) were reduced by up to 60% in various IM-sensitive GIST cell models (GIST-T1, GIST-430, and GIST-882), despite both proteins had remarkable stability, as revealed by cycloheximide experiments. Furthermore, we were able to down-regulate both proteins simultaneously by encapsulating siRNA-YAP1 and siRNA-TAZ in the same WRAP-nanoparticles.
Conclusions
After succeeding in the generation of anti-YAP1/TAZ nanoparticles, we are currently assessing the impact of YAP1/TAZ silencing in their downstream pathways, together with their conjoined effect on cell proliferation and migration. As a last step, we are also evaluating YAP1/TAZ inhibition in combination with IM, aiming to further explore compensation mechanisms.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
C. Serrano: Financial Interests, Personal, Advisory Board: Deciphera Pharmaceuticals, Blueprint Medicines, Immunicum AB, IDRX, CogentBio, Newbay; Financial Interests, Personal, Invited Speaker: PharmaMar, Roche; Financial Interests, Institutional, Research Grant: IDRX; Financial Interests, Institutional, Invited Speaker: Deciphera, IDRX, Newbay, CogentBio; Non-Financial Interests, Personal, Member of Board of Directors: Spanish Group for Sarcoma Research (GEIS), Spanish Society of Medical Oncology (SEOM); Non-Financial Interests, Personal, Other, Faculty member: European Society of Medical Oncology (ESMO); Other, Personal, Other, Travel Grant: PharmaMar, Pfizer, Bayer AG, Gilead. All other authors have declared no conflicts of interest.