Evaluating the efficacy of EFTX-016 ASO in inhibiting the most prevalent lung cancer KRAS mutations

Antisense oligonucleotides (ASOs) regulate cellular gene expression by hybridizing to a complementary RNA sequence and subsequently activating the RNase H1 degradation pathway. Recent advances in oligomer chemical modifications have paved the way for next-generation ASOs with much greater stability in vivo, showing great potential for ASOs as a cancer therapeutic. EFTX-016 ASO is a selective and potent ASO sequence currently under development and designed to knockdown mutant KRAS expression for cancer treatment. In this study, we characterize the efficacy of a screen of variously modified EFTX-016 ASOs to downregulate KRAS mRNA in representative cancer cell lines. We found that free-uptake of the pan-KRAS EFTX-016 ASO sequence (ASO16), which simultaneously targets the four most common KRAS mutations (G12C, G12V, G12D, and G13D), much less potently knocks down KRAS mRNA than the G12C mutant-specific EFTX-016 ASO sequence (ASO16-G12C). Further modifying ASO16-G12C with locked nucleic acid(s) (LNAs) significantly reduced G12C mutant KRAS expression in vitro while moderately sparing wild type activity. Future studies aim to uncover the clinical potential of the ASO16-G12C sequence by continuing to improve its KRAS knockdown efficiency in vitro, wild type KRAS sparing capacity, and evaluating its ability to modulate growth in lung tumor microenvironments.Bachelor of Scienc