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Ref Type Journal Article
PMID (41566838)
Authors Traichel J, Metzger A, Walz M, Feuerstein R, Wohlfeil N, Metzger P, Marx L, Asdih C, Lindenthal A, Seger A, Schrimpf J, Nardella LL, Kowar S, Frew IJ, Halbach S, Kesselring R, Boerries M, Griffin R, Brummer T
Title Novel Syngeneic Cell Lines for Studying High-Risk BRAFV600E-Driven Colorectal Cancer In Vivo.
Journal Vol Issue Date Pages Journal Short Title
Cancer research communications 6 2 2026 Feb 01 320-339 Cancer Res Commun
URL
Abstract Text Combining anti-EGFR antibodies with BRAF/MEK/ERK pathway blockade opened new treatment options for BRAFV600E-driven colorectal cancer. Nevertheless, responses of these poor prognostic cancers are short-lived and heterogeneous, thereby highlighting the unmet need for novel concepts integrating targeted therapy and immuno-oncology. To this end, an immunocompetent mouse model with reliable disease onset and responding to clinically relevant drugs is essential but unavailable. In this study, we generated three cell lines from peritoneal metastases originating from orthotopically transplanted organoids carrying BrafV600E, Trp53R172H, and Apc mutations and characterized their ground state and responses to targeted therapy compounds in detail by RNA sequencing, whole-exome sequencing, and various functional assays. Interestingly, these so-called NaJa lines displayed distinct differentiation states and responses to the clinically relevant RAF inhibitors (RAFi) encorafenib and exarafenib, thereby resembling the clinical heterogeneity of BRAFV600E-driven colorectal cancer. RAFi resistance was overcome by the EGFR family inhibitor afatinib. RAFis also influenced the expression of the antigen presentation machinery, cytokines, and other immunomodulatory factors. Upon retransplantation into syngeneic mice, all NaJa lines established aggressive tumors with distinct tumor microenvironments matching their differentiation states. Thus, the NaJa lines provide a unique tool to study tumor heterogeneity, drug resistance, and the interplay between tumor, stroma, and immune cells in BRAFV600E-driven colorectal cancer.We present three newly isolated syngeneic BRAFV600E-driven colorectal cancer cell lines with distinct in vitro and in vivo phenotypes. They differ in their response to drug treatments, resemble patient tumor heterogeneity, and enable efficient tumor growth in immunocompetent mice for tumor-immune microenvironment studies.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E colorectal cancer sensitive Afatinib + Encorafenib Preclinical - Cell culture Actionable In a preclinical study, Gilotrif (afatinib) and Braftovi (encorafenib) combination treatment suppressed Egfr, Mek, and Erk activation more efficiently than either agent alone, and synergistically inhibited viability and colony formation in cell lines derived from the peritoneal lavage of a microsatellite stable (MSS) colorectal cancer mouse model harboring BRAF V600E along with TP53 R172H (corresponding to R175H in human) and APC loss in culture (PMID: 41566838). 41566838
BRAF V600E colorectal cancer sensitive Exarafenib Preclinical - Cell culture Actionable In a preclinical study, Exarafenib (KIN-2787) inhibited Mek and Erk phosphorylation and suppressed colony formation in cell lines derived from the peritoneal lavage of a microsatellite stable (MSS) colorectal cancer mouse model harboring BRAF V600E along with TP53 R172H (corresponding to R175H in human) and APC loss in culture (PMID: 41566838). 41566838