Abstract 39P
Background
Non-small cell lung cancer (NSCLC), the most common type of lung cancer, can be treated with surgery and chemotherapy. However, surgery alone is often limited, remaining chemotherapy as another treatment option. However, chemoresistance can develop in over time, driven largely by epigenetic alterations. Our aim is to uncover the mechanism behind chemoresistance and to identify novel agents to overcome this resistance.
Methods
In accordance with this, paclitaxel-resistant NSCLC cells were established with dose- escalation strategy. Subsequently characterization of these cells was investigated using viability assays, apoptotic properties by annexin V and caspase 3/7 assays among with cell adhesion and doubling time properties. Additionally, cross resistance and platin sensitivity towards other taxanes and platin agents of these cells were tested. To uncover transcriptomic alterations between parental and resistant cells, RNA-seq was performed and to identify epigenetic vulnerabilities in resistant cell lines, epigenetic drug library screen which has nearly 200 drugs including histone methyltransferase and bromodomain inhibitors, was performed.
Results
As a result, viability experiments confirmed the development of resistance, and apoptotic assays demonstrated that while paclitaxel treatment induces apoptosis in parental cell lines, resistant cells remain viable. Additionally, parental cells were found to proliferate more rapidly and adhere to surfaces more efficiently than their resistant counterparts. Notably, resistant cells exhibited cross-resistance to other taxanes but showed sensitivity to platinum-based agents. RNA sequencing identified ABCB1 as one of the most upregulated genes in resistant cells, and its inhibition demonstrated a synergistic effect in these cell lines. An epigenetic library screening highlighted a group of HDAC inhibitors, along with BRPF inhibitors—a member of the bromodomain reader family—as promising candidates. Subsequent experiments revealed that these inhibitors resensitize resistant cells to taxanes and epidrugs without impacting the parental cell lines.
Conclusions
In conclusion, HDAC and BRPF inhibitors may hold significant potential in reversing resistance.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Koc University.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.