LYN-activating mutations mediate antiestrogen resistance in estrogen receptor-positive breast cancer.
Estrogen receptor-positive (ER(+)) breast cancers adapt to hormone deprivation and become resistant to antiestrogen therapy. Here, we performed deep sequencing on ER(+) tumors that remained highly proliferative after treatment with the aromatase inhibitor letrozole and identified a D189Y mutation in the inhibitory SH2 domain of the SRC family kinase (SFK) LYN. Evaluation of 463 breast tumors in The Cancer Genome Atlas revealed four LYN mutations, two of which affected the SH2 domain. In addition, LYN was upregulated in multiple ER(+) breast cancer lines resistant to long-term estrogen deprivation (LTED). An RNAi-based kinome screen revealed that LYN is required for growth of ER(+) LTED breast cancer cells. Kinase assays and immunoblot analyses of SRC substrates in transfected cells indicated that LYN(D189Y) has higher catalytic activity than WT protein. Further, LYN(D189Y) exhibited reduced phosphorylation at the inhibitory Y507 site compared with LYN(WT). Other SH2 domain LYN mutants, E159K and K209N, also exhibited higher catalytic activity and reduced inhibitory site phosphorylation. LYN(D189Y) overexpression abrogated growth inhibition by fulvestrant and/or the PI3K inhibitor BKM120 in 3 ER(+) breast cancer cell lines. The SFK inhibitor dasatinib enhanced the antitumor effect of BKM120 and fulvestrant against estrogen-deprived ER(+) xenografts but not LYN(D189Y)-expressing xenografts. These results suggest that LYN mutations mediate escape from antiestrogens in a subset of ER(+) breast cancers.
Luis J
LJ
Schwarz
Emily M
EM
Fox
Justin M
JM
Balko
Joan T
JT
Garrett
María Gabriela
MG
Kuba
Mónica Valeria
MV
Estrada
Ana María
AM
González-Angulo
Gordon B
GB
Mills
Monica
M
Red-Brewer
Ingrid A
IA
Mayer
Vandana
V
Abramson
Monica
M
Rizzo
Mark C
MC
Kelley
Ingrid M
IM
Meszoely
Carlos L
CL
Arteaga
D019943:Amino Acid Substitution; D000631:Aminopyridines / Q000819:agonists / Q000494:pharmacology; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D004357:Drug Synergism; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000819:agonists / Q000494:pharmacology; D020125:Mutation, Missense; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000819:agonists / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D013844:Thiazoles / Q000819:agonists / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D018909:src Homology Domains; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
D000631:Aminopyridines; D000069439:Dasatinib; D020847:Estrogen Receptor Modulators; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011960:Receptors, Estrogen; D013844:Thiazoles; D019061:src-Family Kinases; C571178:NVP-BKM120; C060902:lyn protein-tyrosine kinase