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Ref Type Journal Article
PMID (26438159)
Authors Nakanishi Y, Mizuno H, Sase H, Fujii T, Sakata K, Akiyama N, Aoki Y, Aoki M, Ishii N
Title ERK Signal Suppression and Sensitivity to CH5183284/Debio 1347, a Selective FGFR Inhibitor.
Journal Vol Issue Date Pages Journal Short Title
Molecular cancer therapeutics 14 12 2015 Dec 2831-9 Mol Cancer Ther
URL
Abstract Text Drugs that target specific gene alterations have proven beneficial in the treatment of cancer. Because cancer cells have multiple resistance mechanisms, it is important to understand the downstream pathways of the target genes and monitor the pharmacodynamic markers associated with therapeutic efficacy. We performed a transcriptome analysis to characterize the response of various cancer cell lines to a selective fibroblast growth factor receptor (FGFR) inhibitor (CH5183284/Debio 1347), a mitogen-activated protein kinase kinase (MEK) inhibitor, or a phosphoinositide 3-kinase (PI3K) inhibitor. FGFR and MEK inhibition produced similar expression patterns, and the extracellular signal-regulated kinase (ERK) gene signature was altered in several FGFR inhibitor-sensitive cell lines. Consistent with these findings, CH5183284/Debio 1347 suppressed phospho-ERK in every tested FGFR inhibitor-sensitive cell line. Because the mitogen-activated protein kinase (MAPK) pathway functions downstream of FGFR, we searched for a pharmacodynamic marker of FGFR inhibitor efficacy in a collection of cell lines with the ERK signature and identified dual-specificity phosphatase 6 (DUSP6) as a candidate marker. Although a MEK inhibitor suppressed the MAPK pathway, most FGFR inhibitor-sensitive cell lines are insensitive to MEK inhibitors and we found potent feedback activation of several pathways via FGFR. We therefore suggest that FGFR inhibitors exert their effect by suppressing ERK signaling without feedback activation. In addition, DUSP6 may be a pharmacodynamic marker of FGFR inhibitor efficacy in FGFR-addicted cancers.

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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
FGFR2 amp stomach carcinoma no benefit RO4987655 Preclinical - Cell culture Actionable In a preclinical study, FGFR2 amplified gastric carcinoma cell lines were not sensitive to RO4987655 in culture (PMID: 26438159). 26438159
FGFR2 amp colorectal adenocarcinoma decreased response RO4987655 Preclinical - Cell culture Actionable In a preclinical study, FGFR2 amplified colorectal adenocarcinoma cells demonstrated decreased response to RO4987655 in culture (PMID: 26438159). 26438159
FGFR2 N549K endometrial carcinoma no benefit RO4987655 Preclinical - Cell culture Actionable In a preclinical study, endometrial carcinoma cells harboring FGFR2 N549K were not sensitive to RO4987655 in culture (PMID: 26438159). 26438159
FGFR2 K310R FGFR2 N549K endometrial carcinoma no benefit RO4987655 Preclinical - Cell culture Actionable In a preclinical study, endometrial carcinoma cells harboring both FGFR2 K310R and N549K were not sensitive to RO4987655 in culture (PMID: 26438159). 26438159
FGFR1 amp lung small cell carcinoma no benefit Selumetinib Preclinical - Cell culture Actionable In a preclinical study, FGFR1 amplified lung small cell carcinoma cells were not sensitive to Selumetinib (AZD-6244) in culture (PMID: 26438159). 26438159
FGFR2 S252W endometrial carcinoma decreased response Selumetinib Preclinical - Cell culture Actionable In a preclinical study, endometrial carcinoma cells harboring FGFR2 S252W demonstrated decreased sensitivity to Selumetinib (AZD-6244) in culture (PMID: 26438159). 26438159
FGFR2 K310R FGFR2 N549K endometrial carcinoma no benefit RO5126766 Preclinical - Cell culture Actionable In a preclinical study, endometrial carcinoma cells harboring both FGFR2 K310R and N549K were not sensitive to RO5126766 in culture (PMID: 26438159). 26438159
FGFR1 amp lung squamous cell carcinoma no benefit Selumetinib Preclinical - Cell culture Actionable In a preclinical study, FGFR1 amplified lung squamous cell carcinoma cells were not sensitive to Selumetinib (AZD-6244) in culture (PMID: 26438159). 26438159
FGFR3 S249C renal pelvis transitional cell carcinoma no benefit RO4987655 Preclinical - Cell culture Actionable In a preclinical study, renal pelvis transitional cell carcinoma cells harboring FGFR3 S249C were not sensitive to RO4987655 in culture (PMID: 26438159). 26438159
FGFR1 amp lung squamous cell carcinoma no benefit RO5126766 Preclinical - Cell culture Actionable In a preclinical study, FGFR1 amplified lung squamous cell carcinoma cells were not sensitive to RO5126766 in culture (PMID: 26438159). 26438159
FGFR2 S252W endometrial carcinoma sensitive RO5126766 Preclinical - Cell culture Actionable In a preclinical study, RO5126766 inhibited proliferation of endometrial carcinoma cells harboring FGFR2 S252W in culture (PMID: 26438159). 26438159
FGFR2 N549K endometrial carcinoma no benefit RO5126766 Preclinical - Cell culture Actionable In a preclinical study, endometrial carcinoma cells harboring FGFR2 N549K were not sensitive to RO5126766 in culture (PMID: 26438159). 26438159
FGFR2 amp colorectal adenocarcinoma predicted - sensitive RO5126766 Preclinical - Cell culture Actionable In a preclinical study, RO5126766 inhibited proliferation of FGFR2 amplified colorectal adenocarcinoma cells in culture (PMID: 26438159). 26438159
FGFR1 amp lung non-small cell carcinoma no benefit RO5126766 Preclinical - Cell culture Actionable In a preclinical study, FGFR1 amplified non-small cell lung carcinoma cells were not sensitive to RO5126766 in culture (PMID: 26438159). 26438159
FGFR2 S252W endometrial carcinoma decreased response RO4987655 Preclinical - Cell culture Actionable In a preclinical study, endometrial carcinoma cells harboring FGFR2 S252W demonstrated decreased response to RO4987655 in culture (PMID: 26438159). 26438159
FGFR1 amp lung non-small cell carcinoma no benefit RO4987655 Preclinical - Cell culture Actionable In a preclinical study, FGFR1 amplified non-small cell lung carcinoma cells were not sensitive to RO4987655 in culture (PMID: 26438159). 26438159
FGFR2 amp stomach carcinoma no benefit RO5126766 Preclinical - Cell culture Actionable In a preclinical study, FGFR2 amplified gastric carcinoma cell lines were not sensitive to RO5126766 in culture (PMID: 26438159). 26438159
FGFR3 S249C renal pelvis transitional cell carcinoma no benefit RO5126766 Preclinical - Cell culture Actionable In a preclinical study, renal pelvis transitional cell carcinoma cells harboring FGFR3 S249C were not sensitive to RO5126766 in culture (PMID: 26438159). 26438159
FGFR3 S249C renal pelvis transitional cell carcinoma no benefit Selumetinib Preclinical - Cell culture Actionable In a preclinical study, renal pelvis transitional cell carcinoma cells harboring FGFR3 S249C were not sensitive to Selumetinib (AZD-6244) in culture (PMID: 26438159). 26438159
FGFR2 N549K endometrial carcinoma no benefit Selumetinib Preclinical - Cell culture Actionable In a preclinical study, endometrial carcinoma cells harboring FGFR2 N549K were not sensitive to Selumetinib (AZD-6244) in culture (PMID: 26438159). 26438159
FGFR2 amp colorectal adenocarcinoma no benefit Selumetinib Preclinical - Cell culture Actionable In a preclinical study, FGFR2 amplified colorectal adenocarcinoma cells were not sensitive to Selumetinib (AZD-6244) in culture (PMID: 26438159). 26438159
FGFR2 K310R FGFR2 N549K endometrial carcinoma no benefit Selumetinib Preclinical - Cell culture Actionable In a preclinical study, endometrial carcinoma cells harboring both FGFR2 K310R and N549K were not sensitive to Selumetinib (AZD-6244) in culture (PMID: 26438159). 26438159
FGFR1 amp lung squamous cell carcinoma no benefit RO4987655 Preclinical - Cell culture Actionable In a preclinical study, FGFR1 amplified lung squamous cell carcinoma cells were not sensitive to RO4987655 in culture (PMID: 26438159). 26438159
BRAF V600E melanoma sensitive RO5126766 Preclinical - Cell culture Actionable In a preclinical study, RO5126766 inhibited proliferation of melanoma cells harboring BRAF V600E in culture (PMID: 26438159). 26438159
FGFR3 Y373C myeloid neoplasm no benefit Selumetinib Preclinical - Cell culture Actionable In a preclinical study, myeloma cells harboring FGFR3 Y373C were not sensitive to Selumetinib (AZD-6244) in culture (PMID: 26438159). 26438159
FGFR3 Y373C myeloid neoplasm no benefit RO4987655 Preclinical - Cell culture Actionable In a preclinical study, myeloma cells harboring FGFR3 Y373C were not sensitive to RO4987655 in culture (PMID: 26438159). 26438159
FGFR1 amp lung small cell carcinoma no benefit RO5126766 Preclinical - Cell culture Actionable In a preclinical study, FGFR1 amplified lung small cell carcinoma cells were not sensitive to RO5126766 in culture (PMID: 26438159). 26438159
FGFR1 amp lung non-small cell carcinoma no benefit Selumetinib Preclinical - Cell culture Actionable In a preclinical study, FGFR1 amplified non-small cell lung carcinoma cells were not sensitive to Selumetinib (AZD-6244) in culture (PMID: 26438159). 26438159
FGFR3 Y373C myeloid neoplasm no benefit RO5126766 Preclinical - Cell culture Actionable In a preclinical study, myeloma cells harboring FGFR3 Y373C were not sensitive to RO5126766 in culture (PMID: 26438159). 26438159
FGFR2 amp stomach carcinoma sensitive Zoligratinib Preclinical - Cell line xenograft Actionable In a preclinical study, Debio 1347 inhibited tumor growth in cell line xenograft models of FGFR2 amplified gastric carcinoma (PMID: 26438159). 26438159
FGFR1 amp lung small cell carcinoma no benefit RO4987655 Preclinical - Cell culture Actionable In a preclinical study, FGFR1 amplified lung small cell carcinoma cells were not sensitive to RO4987655 in culture (PMID: 26438159). 26438159
BRAF V600E melanoma sensitive RO4987655 Preclinical - Cell culture Actionable In a preclinical study, RO4987655 inhibited proliferation of melanoma cells harboring BRAF V600E in culture (PMID: 26438159). 26438159