Browne, A. T.; McCann, C.; McDaid, W. J.; Lewis, N.; Sridhar, S.; Doherty, G.; Moss, D. Y.; Downs, M.; Marry, S.; Phillips, A.; Brown, C. N.; Speed, A.; Logan, G.; Jellema, G.; Bradford, J.; Davidson, C.; Coyle, V.; Small, D.; Orr, N.; Kennedy, R.; Maguire, S.; Martins, C. P.; Kerr, E. M.

Oncogenic KRAS mutations promote tumorigenesis by constitutive activation of multiple, well-characterised signalling pathways. However, there is significant heterogeneity across mutant KRAS tumours in terms of mutation present, mutant allele abundance and downstream signalling strength. It is unclear whether these variations can impact responses to specific therapies. Here, we demonstrate that ~20% of lung adenocarcinomas (LUAD) show an increase in mutant KRAS dosage (KRASmutant allele fraction > KRASwild-type). Furthermore, we show that KRAS mutant dosage can directly influence clinical outcome and therapeutic susceptibilities in lung cancer. Our findings show that mutant KRAS copy gains specifically affect platinum lung cancer response, promoting resistance to this standard-of-care therapy. Importantly, increases in KRAS mutant dosage are also associated with an increased vulnerability to pS6K inhibition, due to the unique metabolic rewiring of these cells. Together, we show that mutant KRAS dosage contributes to the phenotypic heterogeneity of mutant KRAS NSCLC and that assessment of mutant KRAS content or signalling strength can help optimise treatments strategies for these patients.