UF Investigators Identify Mechanism of Drug Resistance in Non-Small Cell Lung Cancer

Steven J Madore, PhD (ICBR Associate Director for Science)

Summarized from J. Clin. Inv. 2025;135(6); e185149

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. Despite a combination of surgery and chemotherapy, survival rate remains low due to cancer cell metastasis and drug resistance.  Mutations in the oncogene KRAS are frequently found in human cancers, including up to 25% of NSCLC patients. Because the KRAS protein structure limits the ability to develop effective anti-cancer drugs, there are only 2 FDA approved drugs available now that specifically target the KRAS G12C protein mutation. Currently, platinum-based drugs like cisplatin work by damaging the DNA of actively growing cells and are commonly used for treating patients with NSCLC; however, these drugs show limiting effectiveness and fail to elicit a lasting therapeutic response. Reports indicate that NSCLC with KRAS mutations confer platinum resistance and an unfavorable response when compared to those patients with unmutated WT EGFR and KRAS genes.  A recent collaborative study from the laboratories of UF investigators Dr. Zhijian Qian (Dept of Biochemistry and Molecular Biology) and Dr. Lizi Wu (Dept of Molecular Genetics and Microbiology) is aimed at understanding the molecular basis for resistance.  The work was published recently in the Journal of Clinical Investigation (J. Clin. Inv. 2025;135(6); e185149) and was supported by the ICBR Flow Cytometry and Optical Microscopy and Next Generation DNA Sequencing Shared Resources.

Using a cell culture model of NSCLC the authors showed that platinum drug resistance is mediated by KRAS mutation activation of the cellular ERK/JNK signaling pathway. The pathway activation inhibits an important enzyme called ALKBH5 that removes chemical methylation modifications on protein-coding mRNA molecules. This, in turn, stabilizes mRNAs and leads to higher protein synthesis and elevated protein levels in the cell. The levels of two important proteins involved in DNA repair, DDB2 and XPC, are elevated by activation of ERK/JNK pathway. Higher levels of DDBS and XPC proteins enable the NSCLC cells to repair the platinum-induced DNA damage and avoid apoptosis (cell death).  By experimentally blocking KRAS-mutant induced mRNA methylation the authors demonstrate that once resistant KRAS-mutant cells become sensitized to platinum drugs in vitro and in vivo.  This finding offers important information in understanding platinum drug resistance and provides a new promising approach for developing new treatment of NSCLC.