ROR2

Overview

ROR2 (Receptor Tyrosine Kinase-Like Orphan Receptor 2) is a transmembrane receptor involved in non-canonical WNT signaling and developmental morphogenesis. In cancer, ROR2 overexpression is associated with epithelial-to-mesenchymal transition (EMT) and tumor invasiveness. In melanoma, ROR2 was identified as part of a transcriptional program associated with innate resistance to anti-PD-1 checkpoint immunotherapy.

Alterations observed in the corpus

  • ROR2 is upregulated in non-responding pretreatment metastatic melanoma tumors (n=38 WES, n=28 RNA-seq; anti-PD-1 therapy with pembrolizumab or nivolumab); classified as a mesenchymal-transition transcript co-enriched within the IPRES (Innate anti-PD-1 Resistance) transcriptional signature. ROR2 upregulation co-occurs with AXL, WNT5A, LOXL2, TWIST2, TAGLN, and FAP in non-responders. IPRES co-enrichment was present in 9/13 non-responding vs 1/15 responding pretreatment tumors (Fisher P=0.013, OR=4.6). PMID:26997480

Cancer types (linked)

  • SKCM: ROR2 is a component of the IPRES (Innate anti-PD-1 Resistance) transcriptional signature in metastatic melanoma; its overexpression in pretreatment biopsies is associated with non-response to anti-PD-1 therapy. The IPRES transcriptional program is detectable across multiple TCGA cancer types (PAAD, LUAD, COAD, ccRCC) in addition to melanoma. PMID:26997480

Co-occurrence and mutual exclusivity

Therapeutic relevance

  • ROR2, as part of the IPRES program, is a candidate biomarker of innate anti-PD-1 resistance in melanoma; targeting mesenchymal/WNT-pathway components (including ROR2) is proposed as a combination strategy to overcome IPRES-driven resistance to pembrolizumab and nivolumab. IPRES was NOT differentially distributed in anti-CTLA-4 (ipilimumab) responders vs non-responders, suggesting checkpoint-agent specificity. PMID:26997480

Open questions

  • Whether pharmacologic suppression of WNT/ROR2 signaling restores anti-PD-1 sensitivity is unresolved; IPRES is correlative, not yet causally validated. PMID:26997480

Sources

This page was processed by crosslinker on 2026-05-14.