ABSTRACT
Activation of the phosphoinositide 3-kinase (PI3K) pathway occurs frequently in breast cancer. However, clinical results of single-agent PI3K inhibitors have been modest to date. A combinatorial drug screen on multiple PIK3CA mutant cancers with decreased sensitivity to PI3K inhibitors revealed that combined CDK 4/6-PI3K inhibition synergistically reduces cell viability. Laboratory studies revealed that sensitive cancers suppress RB phosphorylation upon treatment with single-agent PI3K inhibitors but cancers with reduced sensitivity fail to do so. Similarly, patients' tumors that responded to the PI3K inhibitor BYL719 demonstrated suppression of pRB, while nonresponding tumors showed sustained or increased levels of pRB. Importantly, the combination of PI3K and CDK 4/6 inhibitors overcomes intrinsic and adaptive resistance leading to tumor regressions in PIK3CA mutant xenografts.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Breast Neoplasms/drug therapy , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Mutation , Phosphoinositide-3 Kinase Inhibitors , Animals , Breast Neoplasms/enzymology , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Proliferation/drug effects , Cell Survival/drug effects , Class I Phosphatidylinositol 3-Kinases , Cyclin-Dependent Kinase 4/genetics , Cyclin-Dependent Kinase 4/metabolism , Cyclin-Dependent Kinase 6/genetics , Cyclin-Dependent Kinase 6/metabolism , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm , Drug Synergism , Female , Genetic Predisposition to Disease , Humans , MCF-7 Cells , Mice , Mice, Nude , Mice, SCID , Molecular Targeted Therapy , Phenotype , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Phosphatidylinositol Phosphates/metabolism , Phosphorylation , Protein Kinase Inhibitors/administration & dosage , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/metabolism , RNA Interference , Retinoblastoma Protein/metabolism , Signal Transduction/drug effects , Time Factors , Transfection , Treatment Outcome , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: The role of serum alpha-fetoprotein (AFP) as a marker for treatment response in patients with hepatocellular carcinoma (HCC) receiving systemic therapy is poorly defined. METHODS: A retrospective study was performed on patients with advanced HCC enrolled in five phase II clinical trials. Serum AFP was prospectively collected at baseline and at different time points through treatment in parallel with radiologic response and clinical outcome. Patients were separated into three groups based on a 50% change in serum AFP from baseline. Overall survival (OS), progression-free survival (PFS), and radiologic responses were compared between groups using log-rank and Wilcoxon tests. RESULTS: Of 144 patients, 107 met the eligibility criteria. Eighteen patients experienced a >50% AFP decline, 57 patients had a >50% AFP increase, and 32 patients had a <50% change in serum AFP in either direction. Compared with patients with a <50% change in serum AFP (median PFS, 5.6 months), patients with a >50% AFP decrease had a longer PFS time (median, 16.9 months; p = .029), whereas those with a >50% increase had a shorter PFS time (median, 2.3 months; p = .038). Patients with a >50% rise in AFP had a shorter OS time than those with a <50% change (median, 6.3 months versus 11.1 months, respectively; p = .004), whereas a >50% AFP decrease was not associated with a significant difference in OS (median, 13.0 months; p = .87). AFP changes were significantly associated with radiologic response. CONCLUSIONS: Our study suggests that serum AFP change during treatment may serve as a useful surrogate marker for clinical outcome in patients with advanced HCC receiving systemic therapy.
