Inhibiting Axl Kinase Receptor: A Novel Therapeutic Approach for Pancreatic Cancer

Pancreatic adenocarcinomas are a leading cause of cancer-related mortality, with a dire five-year survival rate, emphasizing the need for novel therapeutic targets. The receptor tyrosine kinase Axl, a member of the TAM family, has been implicated in various cancer-related processes, including oncogenic transformation and cell survival. Its overexpression is linked to poor outcomes in several cancers, and its role in chronic myelogenous leukemia (CML) is well-documented. Axl's activation by its ligand, Gas6, triggers downstream signaling pathways that promote tumor growth and progression.

Inhibition of Axl using RNAi has been shown to halt tumor growth in cancer models, highlighting its potential as a therapeutic target. HCI-2084, a small molecule inhibitor of Axl kinase, has been developed and exhibits potent activity against Axl with an IC50 of 12 nM, demonstrating efficacy in inhibiting pancreatic cancer cell growth even at low concentrations.

HCI-2084 has been shown to significantly reduce Akt signaling stimulated by GAS6 in pancreatic cancer cells and to inhibit Axl autophosphorylation in Axl-transfected cells. The compound also suppresses Gas6-induced migration and invasion of these cells in vitro. Furthermore, HCI-2084 treatment resulted in a dose-dependent decrease in soluble Axl (sAxl) levels, suggesting that sAxl could serve as a biomarker for the effectiveness of Axl inhibition.

These findings indicate that Axl may be a promising target for pancreatic cancer treatment, and HCI-2084 is a candidate worth investigating further. The compound is currently being evaluated in animal models for its efficacy and pharmacodynamics.