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Ref Type Journal Article
PMID (36759733)
Authors Ruiz-Saenz A, Atreya CE, Wang C, Pan B, Dreyer CA, Brunen D, Prahallad A, Muñoz DP, Ramms DJ, Burghi V, Spassov DS, Fewings E, Hwang YC, Cowdrey C, Moelders C, Schwarzer C, Wolf DM, Hann B, VandenBerg SR, Shokat K, Moasser MM, Bernards R, Gutkind JS, van 't Veer LJ, Coppé JP
Title A reversible SRC-relayed COX2 inflammatory program drives resistance to BRAF and EGFR inhibition in BRAFV600E colorectal tumors.
Journal Vol Issue Date Pages Journal Short Title
Nature cancer 4 2 2023 Feb 240-256 Nat Cancer
URL
Abstract Text BRAFV600E mutation confers a poor prognosis in metastatic colorectal cancer (CRC) despite combinatorial targeted therapies based on the latest understanding of signaling circuitry. To identify parallel resistance mechanisms induced by BRAF-MEK-EGFR co-targeting, we used a high-throughput kinase activity mapping platform. Here we show that SRC kinases are systematically activated in BRAFV600E CRC following targeted inhibition of BRAF ± EGFR and that coordinated targeting of SRC with BRAF ± EGFR increases treatment efficacy in vitro and in vivo. SRC drives resistance to BRAF ± EGFR targeted therapy independently of ERK signaling by inducing transcriptional reprogramming through β-catenin (CTNNB1). The EGFR-independent compensatory activation of SRC kinases is mediated by an autocrine prostaglandin E2 loop that can be blocked with cyclooxygenase-2 (COX2) inhibitors. Co-targeting of COX2 with BRAF + EGFR promotes durable suppression of tumor growth in patient-derived tumor xenograft models. COX2 inhibition represents a drug-repurposing strategy to overcome therapeutic resistance in BRAFV600E CRC.

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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 Dasatinib + Gefitinib + Vemurafenib Preclinical - Pdx & cell culture Actionable In a preclinical study, the combination of Zelboraf (vemurafenib), Iressa (gefitinib), and Sprycel (dasatinib) synergistically inhibited viability in colorectal cancer cell lines harboring BRAF V600E in culture and resulted in greater tumor growth inhibition and tumor regression in patient-derived xenograft (PDX) models to a greater degree than the doublet combinations of Zelboraf (vemurafenib) and Iressa (gefitinib) or Zelboraf (vemurafenib) and Sprycel (dasatinib) (PMID: 36759733). 36759733
BRAF V600E colorectal cancer sensitive Dasatinib + Gefitinib + PLX4720 Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of PLX4720, Iressa (gefitinib), and Sprycel (dasatinib) inhibited tumor growth in colorectal cancer cell line xenograft models harboring BRAF V600E to a greater degree than the combinations of PLX4720 and Iressa (gefitinib) or PLX4720 and Sprycel (dasatinib) (PMID: 36759733). 36759733
BRAF V600E colorectal cancer sensitive Bosutinib + Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, the combination of Zelboraf (vemurafenib) and Bosulif (bosutinib) synergistically inhibited viability in colorectal cancer cell lines harboring BRAF V600E in culture (PMID: 36759733). 36759733
BRAF V600E colorectal cancer sensitive Dasatinib + Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, the combination of Zelboraf (vemurafenib) and Sprycel (dasatinib) synergistically inhibited viability in colorectal cancer cell lines harboring BRAF V600E in culture (PMID: 36759733). 36759733
BRAF V600E colorectal cancer sensitive Gefitinib + PLX4720 + Saracatinib Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of PLX4720, Iressa (gefitinib), and Saracatinib (AZD0530) inhibited tumor growth in colorectal cancer cell line xenograft models harboring BRAF V600E to a greater degree than the combinations of PLX4720 and Iressa (gefitinib) or PLX4720 and Saracatinib (AZD0530) (PMID: 36759733). 36759733
BRAF V600E colorectal cancer sensitive Celecoxib + Encorafenib + Panitumumab Preclinical - Pdx Actionable In a preclinical study, the addition of Celecoxib to the combination of Braftovi (encorafenib) and Vectibix (panitumumab) inhibited tumor growth and induced tumor regression in colorectal cancer patient-derived xenograft (PDX) models harboring BRAF V600E to a greater degree than the combination of Braftovi (encorafenib) and Vectibix (panitumumab) (PMID: 36759733). 36759733
BRAF V600E colorectal cancer sensitive Celecoxib + Trametinib + Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, the addition of Celecoxib to the combination of Zelboraf (vemurafenib) and Mekinist (trametinib) synergistically inhibited viability in colorectal cancer cell lines harboring BRAF V600E in culture (PMID: 36759733). 36759733
BRAF V600E colorectal cancer sensitive Celecoxib + Dabrafenib + Trametinib Preclinical - Pdx Actionable In a preclinical study, the addition of Celecoxib to the combination of Tafinlar (dabrafenib) and Mekinist (trametinib) inhibited tumor growth and induced tumor regression in colorectal cancer patient-derived xenograft (PDX) models harboring BRAF V600E (PMID: 36759733). 36759733
BRAF V600E colorectal cancer sensitive Celecoxib + Gefitinib + Trametinib + Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, the addition of Celecoxib to the combination of Zelboraf (vemurafenib), Mekinist (trametinib), and Iressa (gefitinib) synergistically inhibited viability in colorectal cancer cell lines harboring BRAF V600E in culture (PMID: 36759733). 36759733
BRAF V600E colorectal cancer sensitive Celecoxib + Dabrafenib + Panitumumab + Trametinib Preclinical - Pdx Actionable In a preclinical study, the addition of Celecoxib to the combination of Tafinlar (dabrafenib), Mekinist (trametinib), and Vectibix (panitumumab) inhibited tumor growth and induced tumor regression in colorectal cancer patient-derived xenograft (PDX) models harboring BRAF V600E (PMID: 36759733). 36759733
BRAF V600E colorectal cancer sensitive Celecoxib + Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, the combination of Zelboraf (vemurafenib) and Celecoxib synergistically inhibited viability in colorectal cancer cell lines harboring BRAF V600E in culture (PMID: 36759733). 36759733
BRAF V600E colorectal cancer sensitive Saracatinib + Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, the combination of Zelboraf (vemurafenib) and Saracatinib (AZD0530) synergistically inhibited viability in colorectal cancer cell lines harboring BRAF V600E in culture (PMID: 36759733). 36759733