title: Extracellular Matrix/Integrin Signaling Promotes Resistance to Combined Inhibition of HER2 and PI3K in HER2+Breast Cancer.
abstract: PIK3CAmutations are associated with resistance to HER2-targeted therapies. We previously showed thatHER2+/PIK3CAH1047Rtransgenic mammary tumors are resistant to the HER2 antibodies trastuzumab and pertuzumab but respond to PI3K inhibitor buparlisib (TPB). In this study, we identified mechanisms of resistance to combined inhibition of HER2 and PI3K. TPB-resistant tumors were generated by treatingHER2+/PIK3CAH1047Rtumor-bearing mice long term with the drug combination. RNA sequencing of TPB-resistant tumors revealed that extracellular matrix and cell adhesion genes, including collagen II (Col2a1), were markedly upregulated, accompanied by activation of integrin β1/Src. Cells derived from drug-resistant tumors were sensitive to TBP when grownin vitro, but exhibited resistance when plated on collagen or when reintroduced into mice. Drug resistance was partially reversed by the collagen synthesis inhibitor ethyl-3,4-dihydroxybenzoate. Inhibition of integrin β1/Src blocked collagen-induced resistance to TPB and inhibited growth of drug-resistant tumors. High collagen II expression was associated with significantly lower clinical response to neoadjuvant anti-HER2 therapy in HER2+breast cancer patients. Overall, these data suggest that upregulation of collagen/integrin/Src signaling contributes to resistance to combinatorial HER2 and PI3K inhibition.Cancer Res; 77(12); 3280-92. ©2017 AACR.
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.|Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Ariella B
authors.initials: AB
authors.lastname: Hanker
authors.affiliation: Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Mónica Valeria
authors.initials: MV
authors.lastname: Estrada
authors.affiliation: Department of Medical Oncology, IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Bianchini
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Preston D
authors.initials: PD
authors.lastname: Moore
authors.affiliation: Department of Biomedical Informatics, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Junfei
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Biomedical Informatics, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Feixiong
authors.initials: F
authors.lastname: Cheng
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: James P
authors.initials: JP
authors.lastname: Koch
authors.affiliation: Department of Medical Oncology, IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Gianni
authors.affiliation: Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Darren R
authors.initials: DR
authors.lastname: Tyson
authors.affiliation: Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Violeta
authors.initials: V
authors.lastname: Sánchez
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Brent N
authors.initials: BN
authors.lastname: Rexer
authors.affiliation: Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.|Department of Pathology, Microbiology, and Immunology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Melinda E
authors.initials: ME
authors.lastname: Sanders
authors.affiliation: Department of Biomedical Informatics, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.|Department of Pathology, Microbiology, and Immunology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Stricker
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee. carlos.arteaga@vanderbilt.edu.|Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.|Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D024043:Collagen Type II / Q000378:metabolism*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D019012:Integrin beta1 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016133:Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D024043:Collagen Type II; D019012:Integrin beta1; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases