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|Ref Type||Journal Article|
|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.|
|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.|
|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, Jun 2021).|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|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 Truseltiq (infigratinib) 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 Truseltiq (infigratinib) (PMID: 29203461).||29203461|
|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|