KRAS and EGFR mutations are the most frequent genetic alterations found in lung cancer. While several anti-EGFR therapies have been developed, KRAS is still considered an undruggable target.

An alternative strategy to treat KRAS-mutated tumours relies on targeting KRAS downstream or parallel pathways, as described in a study led by Emilio Casanova, in which an unexpected tumour-suppressive role of STAT3 in KRAS-mutant lung cancer was described.

The investigators used the inducible KRASG12D/+ mouse lung cancer model to analyse tumour development and progression in the presence or absence of STAT3, and performed parallel experiments in a xenograft model with a human lung cancer cell line. “STAT3 has a tumour suppressive function in both lung cancer initiation and progression,” says Casanova, and “in the absence of STAT3, enhanced expression of the chemokine IL-8 increased tumour growth via neoangiogenesis and immune cell infiltration.” Of note, blockade of the IL-8–CXCR2 pathway reverted the observed phenotype in STAT3-deficient tumours.

“These findings elucidate the importance of stratifying patients according to their driver mutation,” highlights Casanova. STAT3 inhibitors are currently being investigated in trials and this study suggests that patients with KRAS-mutated lung tumours might not respond to STAT3 inhibition. However, patients with EGFR-mutated tumours might still benefit from STAT3 inhibition as increased STAT3 activation levels have been detected in these tumours.