PI3K-p110α mediates resistance to HER2-targeted therapy in HER2+, PTEN-deficient breast cancers.
Human epidermal growth factor receptor-2 (HER2) amplification/overexpression (HER2+) frequently co-occurs with PI3K pathway activation in breast tumors. PI3K signaling is most often activated by PIK3CA mutation or PTEN loss, which frequently results in sensitivity to p110α or p110β inhibitors, respectively. To examine the p110 isoform dependence in HER2+, PTEN-deficient tumors, we generated genetic mouse models of breast tumors driven by concurrent Her2 activation and Pten loss coupled with deletion of p110α or p110β. Ablation of p110α, but not p110β, significantly impaired the development of Her2+/Pten-null tumors in mice. We further show that p110α primarily mediates oncogenic signaling in HER2+/PTEN-deficient human cancers while p110β conditionally mediates PI3K/AKT signaling only upon HER2 inhibition. Combined HER2 and p110α inhibition effectively reduced PI3K/AKT signaling and growth of cancer cells both in vitro and in vivo. Addition of the p110β inhibitor to dual HER2 and p110α inhibition induced tumor regression in a xenograft model of HER2+/PTEN-deficient human cancers. Together, our data suggest that combined inhibition of HER2 and p110α/β may serve as a potent and durable therapeutic regimen for the treatment of HER2+, PTEN-deficient breast tumors.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
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Q
Wang
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.|Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
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P
Liu
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
J M
JM
Spangle
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
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T
Von
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
T M
TM
Roberts
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
N U
NU
Lin
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
I E
IE
Krop
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
E P
EP
Winer
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
J J
JJ
Zhao
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy / Q000379:methods; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D058534:Class I Phosphatidylinositol 3-Kinases; D000077341:Lapatinib; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D013844:Thiazoles; C585539:Alpelisib; C484760:PIK3CA protein, human; C497132:PIK3CB protein, human; C508053:ERBB2 protein, human; C494929:PTEN protein, human