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Ref Type Journal Article
PMID (28539475)
Authors Kodack DP, Askoxylakis V, Ferraro GB, Sheng Q, Badeaux M, Goel S, Qi X, Shankaraiah R, Cao ZA, Ramjiawan RR, Bezwada D, Patel B, Song Y, Costa C, Naxerova K, Wong CSF, Kloepper J, Das R, Tam A, Tanboon J, Duda DG, Miller CR, Siegel MB, Anders CK, Sanders M, Estrada MV, Schlegel R, Arteaga CL, Brachtel E, Huang A, Fukumura D, Engelman JA, Jain RK
Title The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation.
Journal Science translational medicine
Vol 9
Issue 391
Date 2017 May 24
URL
Abstract Text Although targeted therapies are often effective systemically, they fail to adequately control brain metastases. In preclinical models of breast cancer that faithfully recapitulate the disparate clinical responses in these microenvironments, we observed that brain metastases evade phosphatidylinositide 3-kinase (PI3K) inhibition despite drug accumulation in the brain lesions. In comparison to extracranial disease, we observed increased HER3 expression and phosphorylation in brain lesions. HER3 blockade overcame the resistance of HER2-amplified and/or PIK3CA-mutant breast cancer brain metastases to PI3K inhibitors, resulting in marked tumor growth delay and improvement in mouse survival. These data provide a mechanistic basis for therapeutic resistance in the brain microenvironment and identify translatable treatment strategies for HER2-amplified and/or PIK3CA-mutant breast cancer brain metastases.

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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
ERBB2 amp breast cancer sensitive Buparlisib Preclinical - Cell line xenograft Actionable In a preclinical study, a breast cancer cell line xenograft model harboring ERBB2 (HER2) amplification demonstrated tumor regression within the mammary fat pad when treated with Buparlisib (BKM120) (PMID: 28539475). 28539475
ERBB2 amp breast cancer sensitive Elgemtumab + Trastuzumab Preclinical - Cell line xenograft Actionable In a preclinical study, breast cancer cell line xenograft models harboring ERBB2 (HER2) amplification were sensitive to the combination of Herceptin (trastuzumab) and LJM716, resulting in a delay of brain lesion growth and improved survival (PMID: 28539475). 28539475
ERBB2 amp breast cancer sensitive Neratinib + Pertuzumab Preclinical - Cell line xenograft Actionable In a preclinical study, breast cancer cell line xenograft models harboring ERBB2 (HER2) amplification were sensitive to the combination of Perjeta (pertuzumab) and Nerlynx (neratinib), resulting in a delay of brain lesion growth and improved survival (PMID: 28539475). 28539475
ERBB2 amp breast cancer sensitive Pertuzumab + Trastuzumab Preclinical - Cell line xenograft Actionable In a preclinical study, breast cancer cell line xenograft models harboring ERBB2 (HER2) amplification were sensitive to the combination of Herceptin (trastuzumab) and Perjeta (pertuzumab), resulting in a delay of brain lesion growth and improved survival (PMID: 28539475). 28539475
PIK3CA H1047R breast cancer sensitive Buparlisib Preclinical - Cell line xenograft Actionable In a preclinical study, a breast cancer cell line xenograft model harboring PIK3CA H1047R demonstrated tumor regression within the mammary fat pad when treated with Buparlisib (BKM120) (PMID: 28539475). 28539475
ERBB2 amp PIK3CA E545K breast cancer sensitive Buparlisib Preclinical - Cell line xenograft Actionable In a preclinical study, a breast cancer cell line xenograft model co-harboring ERBB2 (HER2) amplification and PIK3CA E545K demonstrated tumor regression within the mammary fat pad when treated with Buparlisib (BKM120) (PMID: 28539475). 28539475
ERBB2 amp breast cancer sensitive Elgemtumab + Neratinib Preclinical - Cell line xenograft Actionable In a preclinical study, breast cancer cell line xenograft models harboring ERBB2 (HER2) amplification were sensitive to the combination of LJM716 and Nerlynx (neratinib), resulting in a delay of brain lesion growth and improved survival (PMID: 28539475). 28539475