Targeting Discoidin Domain Receptors DDR1 and DDR2 overcomes matrix‐mediated tumor cell adaptation and tolerance to BRAF‐targeted therapy in melanoma

Abstract

Resistance to BRAF/MEK inhibitor therapy in BRAF V600 -mutated advanced melanoma remains a major obstacle that limits patient benefit. Microenvironment components including the extracellular matrix (ECM) can support tumor cell adaptation and tolerance to targeted therapy; however, the underlying mechanisms remain poorly understood. Here, we investigated the process of matrixmediated drug resistance (MMDR) in response to BRAF V600 pathway inhibition in melanoma. We demonstrate that physical and structural cues from fibroblast-derived ECM abrogate antiproliferative responses to BRAF/MEK inhibition. MMDR is mediated by drug-induced linear clustering of phosphorylated DDR1 and DDR2, two tyrosine kinase collagen receptors. Depletion and pharmacological targeting of DDR1 and DDR2 overcome ECM-mediated resistance to BRAF-targeted therapy. In xenografts, targeting DDR with imatinib enhances BRAF inhibitor efficacy, counteracts druginduced collagen remodeling, and delays tumor relapse. Mechanistically, DDR-dependent MMDR fosters a targetable pro-survival NIK/IKKa/NF-jB2 pathway. These findings reveal a novel role for a collagen-rich matrix and DDR in tumor cell adaptation and resistance. They also provide important insights into environmentmediated drug resistance and a preclinical rationale for targeting DDR signaling in combination with targeted therapy in melanoma.

Bioluminescent zebrafish transplantation model for drug discovery

“…Usually, a trade-off average concentration has to be selected within the activity range of all small-molecule compounds used. This value is generally within the range of 1 -15 µM in most zebrafish in vivo pharmaceutical screens (Bowman and Zon, 2010;Colanesi et al, 2012;Haney et al, 2021;Oprisoreanu et al, 2021;Precazzini et al, 2020).…”

“…Additionally, we demonstrated that the inhibition of proteins related to cell cycle and migration can be useful in targeting leukemic expansion in vivo. Inhibitors targeting discoidin domain receptor 1 (DDR1), BAY-826 and DDR-IN-1 are promising hits as DDR1 inhibition has potential in cancer therapy (Berestjuk et al, 2022;Elkamhawy et al, 2021). Moreover, DDR1 therapeutic targeting in vivo was not yet characterized for the treatment of myeloid leukemia.…”

“…Leukemia is commonly induced by a combined effect of multiple genetic alterations which can hinder the establishment of targeted therapy (Vetrie et al, 2020). Targeting the BCR-ABL1 fusion gene, growth factor receptors (GFRs) and also the RAS-RAF-MEK-ERK pathway, all belong to strategies used in the treatment of myeloid leukemias (Bhullar et al, 2018). We found 17 compounds (used again either at 10 µM or 1 µM) as hits in our screen looking at the inhibition of leukemia cancer cell growth in vivo.…”

“…For more than a decade, zebrafish (Danio rerio) has accompanied the mouse as another promising model animal for human tumor xenograft assays (Cagan et al, 2019;Kirchberger et al, 2017;Topczewska et al, 2006). Drug discovery connected to inhibitor screening is a field where zebrafish have a great potential (Bowman and Zon, 2010;MacRae and Peterson, 2015;Patton et al, 2021b). With the smallsized transparent embryos lacking the adaptive immune system, it is feasible to graft and track high numbers of experimental animals in a relatively short time.…”

The Molecular Interaction of Collagen with Cell Receptors for Biological Function

“…Further, DDR1 inhibition prevents EMT through the MKK7 and Pyk2 signaling pathways, which cause apoptosis in the prostate tumor cell. Accordingly, DDR1 activates EMT via stimulating the protein expression of N-cadherin and vimentin and phosphorylation of Pyk2 and MKK7 in prostate cancer [ 154 ].…”