Abstract: CRISPR-Enhanced Chemotherapy for Overcoming Drug Resistance in Squamous Non-Small Cell Lung Cancer

Lung cancer is the leading cause of cancer-related mortality and is commonly resistant to standard chemotherapy treatments.1 Non-small cell lung cancer is the most common type of lung cancer, accounting for 80% of cases.2 The standard treatment for non-small cell lung cancer is chemotherapy treatments, such as cisplatin and gemcitabine.3 However, these standard cancer treatments increase the risk of developing more harmful side effects and present a risk of recurrence due to the lack of precision of chemotherapy. These treatments are often resisted by the rapidly growing cancer cells due to intrinsic or acquired resistance mechanisms. This results in parts of the tumor being left behind and instances of recurrence. We propose a treatment strategy that integrates traditional chemotherapy with CRISPR-Cas9 gene editing to overcome drug resistance and improve tumor response. CRISPR-Cas9 has been tested previously to edit the genes of T cells so they have an enhanced immune response to cancer cells.4 Building on this research, CRISPR-Cas9 will be delivered intravenously using lipid nanoparticles, analyze the genome of a tumour, identify and knock out the specific resistance genes,5 ERCC1 and MDR1, associated with cisplatin resistance and drug efflux, respectively.6 By disrupting these pathways, tumor cells become more vulnerable to DNA damage and drug accumulation, significantly enhancing the cytotoxic efficacy of cisplatin-based chemotherapy. A treatment plan following the CRISPR and chemotherapy treatments, would include continuous monitoring of progress via PET-CT and biopsies. Additionally, pulmonary function and side effects will be monitored to ensure treatment is progressing effectively. This treatment plan allows for patients to receive a lower dose of chemotherapy and minimizes the harmful side effects that usually accompany chemotherapy.