JAK inhibitors in KRAS driven Lung Adenocarcinoma

Lung cancer is a fatal disease responsible for the most of cancer-related deaths worldwide. Lung cancer can be divided in several subtypes, being lung adenocarcinoma the most abundant. Approximately half of lung adenocarcinomas contains mutations in two oncogenes, EGFR and KRAS, which drive tumorigenesis. Patient suffering of lung adenocarcinomas having a mutation in the EGFR oncogene can be treated with molecules blocking EGFR. Unfortunately, at the moment there are not a KRAS inhibitors which can be used to treat lung adenocarcinoma patients harboring KRAS mutation (1/3rd) in the clinics. Treatment of KRAS mutated lung adenocarcinomas relays on inhibition of KRAS downstream effectors or KRAS cooperating signaling pathways. In this sense, activation of the JAK/STAT signaling pathway has been associated with lung tumorigenesis and it may cooperate with KRAS by facilitating that tumors escape the surveillance of the immune system. Within this proposal, we will validate JAK/STAT inhibition in combination with drugs than re-activate the immune system as an option for therapeutic treatment of KRAS mutated lung adenocarcinomas. The final aim of this study will be to develop new therapeutic options to treat KRAS mutated lung cancer.

Lung cancer remains the leading cause of cancer deaths worldwide. The most common type, lung adenocarcinoma, often carries mutations in a gene called KRAS. These mutations help cancer grow and make it harder to treat. Unfortunately, only two drugs directly targeting KRAS are currently approved for widespread use, leaving patients with limited treatment options. Our project explored a different approach. Instead of targeting KRAS directly, we focused on blocking a related signaling pathway-JAK/STAT-that helps cancer survive and spread. We used a drug called ruxolitinib, which blocks JAK1/2 proteins, and tested it in preclinical models of KRAS-driven lung cancer. We found that ruxolitinib effectively slowed tumor growth. It worked by directly affecting cancer cells and by changing the tumor environment in a way that made it less supportive of cancer. These findings suggest that targeting the JAK/STAT pathway could offer a promising new treatment option for patients with KRAS-driven lung cancer, especially when combined with therapies that boost the immune system.