New approach for an “undruggable” cancer target?

Tailoring therapies to patients by targeting specific mutations has transformed the treatment landscape and prolonged survival for people with cancer. However, one target in particular, KRAS, has remained elusive. Mutated KRAS is found in over 1 in 3 lung cancers called adenocarcinomas. Researchers in Melbourne wanted to discover a new way to treat KRAS-positive lung cancers, and their approach focused on the differences between these cancers, rather than the similarities.

Best et al. reported this week in Nature Communications that the behaviour of KRAS-positive lung adenocarcinomas depends on which other mutation they have. They looked at mutated TP53 or KEAP1 which, alongside KRAS, appear to make adenocarcinomas more aggressive. Tumours with mutated KRAS and TP53 were flooded with immune cells, while those with KRAS and KEAP1 used a different process to make energy for tumour growth. By tailoring treatment, researchers prevented tumour growth by either depleting immune cells or blocking KEAP1-related energy production. While hypothesis-generating, this study reminds us that a magic bullet approach of targeting a single mutation is not always the answer. The solution may lie in better understanding how mutations commonly found together are associated with downstream effects, which may be targeted using approaches not previously considered.