Harnessing endogenous RTK inhibitors for anti-cancer treatment

Aberrant receptor tyrosine kinase (RTK) signaling is a hallmark of GBM and sustains unlimited proliferation and enhanced motility. Targeted agents against RTKs including monoclonal antibodies and small molecule inhibitors, were largely unsuccessful in GBM patients, most likely due to molecular heterogeneity and limited drug delivery to the brain. Furthermore redundancy of signaling pathways and compensatory molecular mechanisms lead to the development of treatment resistance. The transmembrane protein LRIG1 (Leucine-rich repeat and immunoglobulin-like domain) is an endogenous regulator of RTKs during organ development and stem cell homeostasis. We have shown that the soluble part of LRIG1 potently inhibits GBM growth in vitro and in vivo in patient-derived GBM with variable RTK expression. We have identified AXL as a novel target of LRIG1 and have shown that direct protein interaction leads to receptor downregulation. Our current efforts aim to identify the molecular mechanism of LRIG1 induced RTK regulation and the minimal active domain of the protein that might be harnessed as a novel anti-cancer agent with pan-RTK inhibitory activity.

This project is supported by the Luxembourg National Research Fund (PRIDE15/10675146/CANBIO), Télévie FNRS, and Fondation Cancer Luxembourg.

Key publications

Neirinckx et al., NOA, 2019 pubmed
Neirinckx et al., BBA, 2017 pubmed
Johansson et al., Neuro Oncol, 2013 pubmed