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Ref Type Journal Article
PMID (29203461)
Authors Liu H, Murphy CJ, Karreth FA, Emdal KB, White FM, Elemento O, Toker A, Wulf GM, Cantley LC
Title Identifying and Targeting Sporadic Oncogenic Genetic Aberrations in Mouse Models of Triple-Negative Breast Cancer.
Journal Cancer discovery
Vol 8
Issue 3
Date 2018 Mar
URL
Abstract Text Triple-negative breast cancers (TNBC) are genetically characterized by aberrations in TP53 and a low rate of activating point mutations in common oncogenes, rendering it challenging in applying targeted therapies. We performed whole-exome sequencing (WES) and RNA sequencing (RNA-seq) to identify somatic genetic alterations in mouse models of TNBCs driven by loss of Trp53 alone or in combination with Brca1 Amplifications or translocations that resulted in elevated oncoprotein expression or oncoprotein-containing fusions, respectively, as well as frameshift mutations of tumor suppressors were identified in approximately 50% of the tumors evaluated. Although the spectrum of sporadic genetic alterations was diverse, the majority had in common the ability to activate the MAPK/PI3K pathways. Importantly, we demonstrated that approved or experimental drugs efficiently induce tumor regression specifically in tumors harboring somatic aberrations of the drug target. Our study suggests that the combination of WES and RNA-seq on human TNBC will lead to the identification of actionable therapeutic targets for precision medicine-guided TNBC treatment.Significance: Using combined WES and RNA-seq analyses, we identified sporadic oncogenic events in TNBC mouse models that share the capacity to activate the MAPK and/or PI3K pathways. Our data support a treatment tailored to the genetics of individual tumors that parallels the approaches being investigated in the ongoing NCI-MATCH, My Pathway Trial, and ESMART clinical trials. Cancer Discov; 8(3); 354-69. ©2017 AACR.See related commentary by Natrajan et al., p. 272See related article by Matissek et al., p. 336This article is highlighted in the In This Issue feature, p. 253.

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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
FGFR2 DNM3 FGFR2 - DNM3 fusion gain of function FGFR2-DNM3 results from the fusion of FGFR2 and DNM3, resulting in FGFR2 activation, increased PI3K and MAPK pathway signaling, and increased colony formation in culture (PMID: 29203461). FGFR2-DNM3 has been identified in triple-receptor negative breast cancer (PMID: 29203461).
FGFR2 TNS1 FGFR2 - TNS1 fusion unknown FGFR2-TNS1 results from the fusion of FGFR2 and TNS1 (PMID: 29203461). FGFR2-TNS1 has been identified in triple-receptor negative breast cancer (PMID: 29203461), but has not been biochemically characterized and therefore, the effect on protein function is unknown (PubMed, Nov 2020).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 - TNS1 triple-receptor negative breast cancer no benefit Buparlisib Preclinical - Cell line xenograft Actionable In a preclinical study, triple-receptor negative breast cancer xenograft models harboring FGFR2-TNS1 demonstrated stable disease upon treatment with Buparlisib (BKM120), but also exhibited general toxicity (PMID: 29203461). 29203461
FGFR2 - TNS1 triple-receptor negative breast cancer sensitive Buparlisib + Infigratinib Preclinical - Cell line xenograft Actionable In a preclinical study, triple-receptor negative breast cancer xenograft models harboring FGFR2-TNS1 demonstrated rapid and complete tumor regression when treated with the combination of Infigratinib (BGJ398) and Buparlisib (BKM120) (PMID: 29203461). 29203461
FGFR2 - TNS1 triple-receptor negative breast cancer sensitive Infigratinib Preclinical - Cell line xenograft Actionable In a preclinical study, triple-receptor negative breast cancer xenograft models harboring FGFR2-TNS1 demonstrated tumor regression when treated with Infigratinib (BGJ398) (PMID: 29203461). 29203461