Journal
MOLECULAR CANCER THERAPEUTICS
Volume 13, Issue 1, Pages 60-70Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-13-0518
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Funding
- F31 NIH/NCI [F31CA165819]
- NIH [P30-CA 16672, PO1-CA099031, RO1-CA112567-06]
- Susan G. Komen Breast Cancer Foundation Promise Grant [KG091020]
- Cancer Prevention Research Institute of Texas Grant [RP100726]
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Although the HER2-targeting agents trastuzumab and lapatinib have improved the survival of patients with HER2-positive breast cancer, resistance to these targeted therapies is a major challenge. To investigate mechanisms of acquired lapatinib resistance, we generated acquired lapatinib resistance cell models by extended exposure of two HER2-positive breast cancer cell lines to lapatinib. Genomic and proteomic analyses revealed that lapatinib-resistant breast cancer cells gained additional phosphoinositide 3-kinase (PI3K) activation through activating mutation in PI3K p110 alpha and/ or increasing protein expression of existing mutant p110 alpha. p110 alpha protein upregulation in lapatinib-resistant cells occurred through gene amplification or posttranscriptional upregulation. Knockdown of p110 alpha, but not p110 beta, the other PI3K catalytic subunit present in epithelial cells, inhibited proliferation of lapatinib-resistant cells, especially when combined with lapatinib. Lapatinib-resistant xenograft growth was inhibited persistently by combination treatment with the p110 alpha-selective PI3K inhibitor BYL719 and lapatinib; the drug combination was also well tolerated in mice. Mechanistically, the combination of lapatinib plus BYL719 more effectively inhibited Akt phosphorylation and, surprisingly, Erk phosphorylation, than either drug alone in the resistance model. These findings indicate that lapatinib resistance can occur through p110a protein upregulation-mediated, and/ or mutation-induced, PI3K activation. Moreover, a combinatorial targeted therapy, lapatinib plus BYL719, effectively overcame lapatinib resistance in vivo and could be further tested in clinical trials. Finally, our findings indicate that p110 beta may be dispensable for lapatinib resistance in some cases. This allows the usage of p110 alpha-specific PI3K inhibitors and thus may spare patients the toxicities of pan-PI3K inhibition to allow maximal dosage and efficacy.
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