A form of lung cancer long considered practically untreatable may finally have a targeted line of attack. A team led by oncologist Colin Lindsay of The Christie NHS Foundation Trust and cell biologist Angeliki Malliri of the University of Manchester has found a way to strike directly at tumours driven by a rare variant of the KRAS gene. Their results appeared in the journal Cancer Discovery.
In healthy cells, the KRAS gene acts like a switch that turns cell division on and off. When a mutation jams it permanently in the "on" position, the resulting protein keeps firing growth signals and tumours form. In non-small cell lung cancer (NSCLC), which the researchers say accounts for around a fifth of all cancer deaths worldwide, such KRAS faults are among the most common causes.
While the widespread KRAS G12C mutation can now be curbed with medication, the rarer changes at so-called codon 13 – including KRAS G13C – had remained out of reach. They make up only about five to seven percent of KRAS-driven lung carcinomas, but they frequently occur alongside other aggressive mutations in genes such as BRAF, NF1, STK11 and KEAP1 that further accelerate tumour growth.
This is precisely where the experimental compound RMC-8839 comes in, which the team studied together with the US biotech company Revolution Medicines. The molecule is tailored specifically to KRAS G13C and shuts down its growth signals. In the laboratory it halted activation of the mutated protein and slowed the proliferation of cancer cells.
A second observation proved especially consequential: tumours carrying the codon 13 mutation were unusually sensitive to chemotherapy. When the researchers combined RMC-8839 with such treatment, the growths shrank dramatically in preclinical cancer models – and in some cases disappeared entirely.
For now the data come from cell and animal models; clinical trials in patients must still confirm the benefit. The group nonetheless expects that the move into the clinic could come relatively quickly. Worldwide, an estimated 11,400 people a year whose lung cancer stems from a codon 13 mutation could benefit – another building block of precision oncology, which tailors treatment to a tumour's genetic profile rather than merely the organ it started in.