DDR1 (discoidin domain receptor tyrosine kinase 1) drives glioblastoma therapy resistance by modulating autophagy

Abstract

Therapy resistance of tumor cells is a major obstacle for efficient anticancer treatment approaches and has been attributed to tumor heterogeneity as well as genetic and epigenetic changes. Accumulating evidence demonstrates that tumor cell adhesion to the extracellular matrix acts as an additional essential factor conferring tumor cell resistance to both radio- and chemotherapeutic intervention. Our recent study demonstrates that DDR1 (discoidin domain receptor tyrosine kinase 1) elicits therapy resistance of glioblastoma multiforme (GBM) stem-like and bulk cells through its adhesion to extracellular matrix and the subsequent modulation of macroautophagy/autophagy. Mechanistically, DDR1 associates with a YWHA/14-3-3-BECN1-AKT1 multiprotein complex favoring pro-survival/anti-autophagic and resistance-mediating AKT-MTOR signaling. In turn, inhibition of DDR1 sensitizes glioblastoma cells to radio- and chemotherapy by inducing autophagy. Collectively, our study suggests that DDR1 may be a potential target for sensitizing glioblastoma cells to combination therapies through its efficient induction of autophagic cell death. Abbreviations: AKT1: AKT serine/threonine kinase 1; ATG14: autophagy related 14; BECN1: Beclin 1; DDR1: discoidin domain receptor tyrosine kinase 1; ECM: extracellular matrix; GBM: glioblastoma multiforme; MTOR: mechanistic target of rapamycin kinase; PDGFR: platelet derived growth factor receptor; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; RPTOR: regulatory associated protein of MTOR complex 1; RICTOR: RPTOR independent companion of MTOR complex 2.

Keywords: Autophagy; discoidin domain receptor tyrosine kinase 1; glioblastoma; radiochemotherapy; therapy resistance.

Figure 1.

Inhibition of DDR1 modulates radiosensitization through autophagy. Schematic representation of DDR1 function in GBM cells upon radiochemotherapy. Under basal conditions, DDR1 associates with YWHA/14–3-3-BECN1-AKT1 protein complex, mediates pro-survival DDR1 signaling and radiochemoresistance. Upon DDR1 inhibition, the YWHA/14–3-3-BECN1-AKT1 protein complex dissociates from DDR1. BECN1 interacts with PIK3C3/VPS34 and ATG14 and induces autophagic cell death forradiochemosensitization. P, phosphorylation.