Reference Detail

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.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

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	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	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 + 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 + 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	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	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 + 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	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	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 + 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	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	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