Association between gain-of-function mutations in PIK3CA and resistance to HER2-targeted agents in HER2-amplified breast cancer cell lines.
BACKGROUND
The mechanism of resistance to human epidermal growth factor receptor 2 (HER2)-targeted agents has not been fully understood. We investigated the influence of PIK3CA mutations on sensitivity to HER2-targeted agents in naturally derived breast cancer cells.


METHODS
We examined the effects of Calbiochem (CL)-387,785, HER2 tyrosine kinase inhibitor, and trastuzumab on cell growth and HER2 signaling in eight breast cancer cell lines showing HER2 amplification and trastuzumab-conditioned BT474 (BT474-TR).


RESULTS
Four cell lines with PIK3CA mutations (E545K and H1047R) were more resistant to trastuzumab than the remaining four without mutations (mean percentage of control with 10 microg/ml trastuzumab: 58% versus 92%; P = 0.010). While PIK3CA-mutant cells were more resistant to CL-387,785 than PIK3CA-wild-type cells (mean percentage of control with 1 microM CL-387,785: 21% versus 77%; P = 0.001), CL-387,785 retained activity against BT474-TR. Growth inhibition by trastuzumab and CL-387,785 was more closely correlated with changes in phosphorylation of S6K (correlation coefficient, 0.811) than those of HER2, Akt, or ERK1/2. Growth of most HER2-amplified cells was inhibited by LY294002, regardless of PIK3CA genotype.


CONCLUSIONS
PIK3CA mutations are associated with resistance to HER2-targeted agents. PI3K inhibitors are potentially effective in overcoming trastuzumab resistance caused by PIK3CA mutations. S6K phosphorylation is a possibly useful pharmacodynamic marker in HER2-targeted therapy.
Kataoka
Y
Y
Hospital Pharmacy.
Mukohara
T
T
Cancer Center, Kobe University Hospital; Medical Oncology, Department of Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe. Electronic address: mukohara@med.kobe-u.ac.jp.
Shimada
H
H
Research Center for Innovative Oncology, National Cancer Hospital East, Kashiwa, Japan.
Saijo
N
N
Research Center for Innovative Oncology, National Cancer Hospital East, Kashiwa, Japan.
Hirai
M
M
Hospital Pharmacy.
Minami
H
H
Cancer Center, Kobe University Hospital; Medical Oncology, Department of Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe.
D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000008:administration & dosage / Q000494:pharmacology; D058534:Class I Phosphatidylinositol 3-Kinases; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D005784:Gene Amplification / Q000502:physiology; D006801:Humans; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D020125:Mutation, Missense / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D002867:Chromones; D058534:Class I Phosphatidylinositol 3-Kinases; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D019893:Ribosomal Protein S6 Kinases; D000068878:Trastuzumab; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C484760:PIK3CA protein, human; C508053:ERBB2 protein, human