Issues

Skoulidis, Goldberg, Greenawalt, and colleagues linked STK11 mutations to PD-1 inhibitor resistance in KRAS-mutant lung cancer. Patients with lung cancer harboring co-occurring STK11 and KRAS alterations had a lower response rate to PD-1/PD-L1 blockade than patients with co-occurring KRAS and TP53 alterations or KRAS mutations alone. STK11 alterations were enriched in PD-L1–negative tumors with an intermediate to high tumor mutation burden. However, STK11 alterations were also associated with primary resistance to PD-1 blockade in patients with PD-L1–positive tumors. Stk11 deletion induced de novo resistance to PD-1 inhibition in a mouse model of KRAS-mutant lung adenocarcinoma. These results demonstrate that STK11 alterations confer primary resistance to PD-1/PD-L1 blockade and suggest that genomic profiling may identify patients likely to benefit from PD-1 blockade. For details, please see the article by Skoulidis, Goldberg, Greenawalt, and colleagues on page 822.