Norton Thoracic Institute researchers believe they have discovered a new approach to treating an aggressive and difficult-to-treat type of lung cancer. They published their study (“WEE1 Kinase Inhibitor AZD1775 Has Pre-clinical Efficacy in LKB1-Deficient Non–Small Cell Lung Cancer”) in Cancer Research. The team found that lung cancer patients whose tumors harbor specific genomic mutations are more likely to benefit from a novel drug, AZD1775, an inhibitor against the G2/M checkpoint protein WEE1, that is currently in clinical trials.
“The tumor suppressor serine/threonine kinase 11 (LKB1/STK11) is one of the most frequently mutated genes in non–small cell lung cancer (NSCLC) and is commonly co-mutated with oncogenic KRAS mutations. We investigated the pre-clinical effects of AZD1775 in the context of KRAS/LKB1 in NSCLC,” write the investigators. “Using NSCLC cell lines, we found that AZD1775 alone and in combination with DNA-damaging agents (e.g., cisplatin and radiation) decreased tumor cell viability in LKB1-deficient NSCLC cells….In a genetically engineered mouse model of mutant Kras with concomitant loss of Lkb1, combined AZD1775 and cisplatin extended overall survival compared with cisplatin alone.”
Tumors harboring mutations in KRAS and/or LKB1 are common among lung adenocarcinomas, the most common histotype of lung cancer, which remains the leading cause of cancer-related mortality. These mutations are associated with aggressive disease progression and poor patient prognosis and have been historically difficult to treat.
“We hope these findings spur new explorations for targeting this molecular subgroup, leading to better clinical trial design in the near future,” said Landon Inge, Ph.D., adding that AZD1775 works as a WEE1 kinase inhibitor.
The eventual goal for this research is to continue to identify those patients who will most likely benefit from the use of this type of therapy and to inform future clinical trial design by selecting lung cancer patients with difficult-to-treat molecular alterations.