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Enhanced PI3K P110a Signaling Confers Acquired Lapatinib Resistance That Can Be Effectively Reversed by a P110a-Selective PI3K Inhibitor

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Enhanced PI3K P110a Signaling Confers Acquired Lapatinib Resistance That Can Be Effectively Reversed by a P110a-Selective PI3K Inhibitor Published OnlineFirst November 18, 2013; DOI: 10.1158/1535-7163.MCT-13-0518 Molecular Cancer Small Molecule Therapeutics Therapeutics Enhanced PI3K p110a Signaling Confers Acquired Lapatinib Resistance That Can Be Effectively Reversed by a p110a-Selective PI3K Inhibitor Samuel W. Brady1,2, Jian Zhang1, Daniel Seok1, Hai Wang1, and Dihua Yu1,2 Abstract 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 phosphoinosi- tide 3-kinase (PI3K) activation through activating mutation in PI3K p110a and/or increasing protein expression of existing mutant p110a.p110a protein upregulation in lapatinib-resistant cells occurred through gene amplification or posttranscriptional upregulation. Knockdown of p110a,butnotp110b,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 p110a-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 p110b may be dispensable for lapatinib resistance in some cases. This allows the usage of p110a-specific PI3K inhibitors and thus may spare patients the toxicities of pan-PI3K inhibition to allow maximal dosage and efficacy. Mol Cancer Ther; 13(1); 60–70. Ó2013 AACR. Introduction clinical outcomes in patients having HER2-positive breast HER2 is a receptor tyrosine kinase (RTK) overexpressed cancer (5–7). Yet resistance to the dual EGFR/HER2 in 25% of breast cancers (1). HER2 overexpression leads to kinase inhibitor lapatinib frequently occurs (8). Therapeu- ligand-independent receptor dimerization and phosphor- tic options for such patients are limited; therefore identi- ylation, including phosphorylation of EGFR, HER2, and fying resistance mechanisms is crucial to develop effective HER3 (2, 3). This in turn promotes activation of phos- treatments for these patients. Activating mutations in the p110a catalytic subunit phoinositide 3-kinase (PI3K)-Akt and mitogen-activated PIK3CA protein kinase signaling, among other pathways, to pro- of PI3K ( ) occur in 25% of HER2-positive breast mote cell proliferation and survival (4). Targeted agents cancers (9) and are believed to promote lapatinib (and against HER2 (e.g., lapatinib) have significantly improved trastuzumab) resistance through Akt activation (9–12). However, some HER2-positive breast cancers and cell lines with PI3K mutations are lapatinib-sensitive (13– Authors' Affiliations: 1Department of Molecular and Cellular Oncology, 15). Here, we show that such cancers may acquire The University of Texas MD Anderson Cancer Center; and 2Cancer Biology resistance to lapatinib by further increasing PI3K sig- Program, The University of Texas Health Science Center at Houston Graduate School of Biomedical Sciences, Houston, Texas naling output through either upregulation of an exist- ing PI3K p110a mutant and/or a secondary p110a Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). mutation event. These findings could help differentiate HER2-positive, PI3K-mutant breast cancers that are Corresponding Author: Dihua Yu, Department of Molecular and Cellular Oncology, MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, lapatinib-sensitive from those that are lapatinib-resis- TX 77030. Phone: 713-792-3636; Fax: 713-792-4454; E-mail: tant. The results suggest that targeting the PI3K muta- [email protected] tion can be an effective strategy to overcome lapatinib doi: 10.1158/1535-7163.MCT-13-0518 resistance in HER2-positive and PI3K-mutant breast Ó2013 American Association for Cancer Research. cancers. 60 Mol Cancer Ther; 13(1) January 2014 Downloaded from mct.aacrjournals.org on September 25, 2021. © 2014 American Association for Cancer Research. Published OnlineFirst November 18, 2013; DOI: 10.1158/1535-7163.MCT-13-0518 PI3K p110a Signaling Promotes Lapatinib Resistance Materials and Methods Western blot analysis Parental, lapatinib-resistant, and stable cell lines LapR cells underwent lapatinib withdrawal for 1 BT474.m1 cells (BT474 hereafter) were described pre- week before experiments and drugs were given in fresh viously (16). UACC893 cells were from American Type medium. Protein was isolated from cells and 30 mg protein Culture Collection. Lapatinib-resistant (LapR) cells were per sample was analyzed by Western blot analysis as we derived by treating parental cells with 2.1 mmol/L lapa- have done previously (16). Antibodies were from GE tinib for >9 months (BT474) or increasing doses until Healthcare (secondary antibodies), Sigma (a-tubulin), reaching 2.1 mmol/L for a total of >5 months (UACC893). or Cell Signaling Technology. Films were scanned into Cell lines were authenticated by the MD Anderson Char- Adobe Photoshop; quantification was performed in Ima- acterized Cell Line Core Facility by short tandem repeat geJ. For siRNA knockdown efficiency, cells were har- analysis (March 2013). HA-PIK3CA wild-type and vested for Western blot analysis 3 days post-transfection. H1047R (Addgene plasmids 12522, 12524) from Dr. Jean Zhao (Dana-Farber Cancer Institute, Boston, MA; ref. 17) Quantitative PCR were cloned into pLVX EF1a-IRES-ZsGreen (Clontech). RNA isolated with TRIzol (Life Technologies) or RNA- HA-PIK3CA E542K was generated by site-directed zol (Molecular Research Center, Inc.) was reverse-tran- mutagenesis. Following lentiviral infection cells were scribed using SuperScript III (Life Technologies). gDNA FACS-sorted to isolate ZsGreen-expressing cells. was isolated as with whole-exome sequencing. Quantita- tive PCR (qPCR) was done using SYBR FAST (Kapa Proliferation assays and siRNA transfection Biosystems) or iQ SYBR Green or iTaq Universal SYBR For MTT proliferation assays, 3,000–10,000 cells per Green Supermix (Bio-Rad). Primers recognizing PIK3CA well were plated in 96-well plates, generally in triplicate E542K allele were: (forward) 50-CAATGAATTAAGG- for each treatment. siRNA (Sigma), if used, was trans- GAAAATGACA-30; (reverse) 50-CTTTCTCCTGCTCAG- fected 1 to 2 days later at 10 nmol/L using PepMute TGATTCT-30. These and other gDNA-specific primers (SignaGen). Medium was replaced the next day with used (wild-type PIK3CA and LINE1) were described pre- drug- or vehicle-containing medium. When siRNA was viously (18, 19). cDNA-specific primers were designed not used, drug was added 1 to 2 days after plating. using standard techniques. Dimethyl sulfoxide (DMSO) concentration was 0.1% and equal between treatments. Three to five days after Cell-cycle analysis drug addition, 25 to 50 mL per well of 5 mg/mL MTT After indicated treatments, cells were harvested, fixed (Sigma) was added. One to three hours later, medium was in cold 75% ethanol, 25% PBS 40 minutes on ice, washed, replaced with 100 mL DMSO and readings were per- stained with 33 mg/mL propidium iodide in PBS 20 formed after solubilization. Of note, 650 nm background minutes at 37 C, and analyzed by flow cytometry. Doub- optical densities (OD) were subtracted from 570 nm lets were gated out. readings and normalized to vehicle. For crystal violet staining to visualize proliferation, 300,000 cells per well Xenograft studies were plated in 6-well plates. One to 2 days later, siRNA Six- to 8-week-old female Swiss nude mice (MD Ander- transfection was performed and drugs were given in son Department of Experimental Radiation Oncology) fresh medium one day after transfection. After 3 to 5 received mammary fat pad (mfp) injections of 4.5 million days of drug treatment, cells were fixed with 0.5% BT474 LapR cells in 100 mL 1:1 serum-free medium and crystal violet, 6% glutaraldehyde for 30 to 60 minutes, growth factor-reduced Matrigel (BD Biosciences). Two followed by wash and imaging of wells. Lapatinib was tumors per mouse were injected on opposing middle withdrawn from LapR cells for 1weekbefore mfps. Next day, mice were treated with 31 mg estrogen experiments. intraperitoneally (estradiol cypionate; Pfizer) to support tumor growth. Seven days later, tumors were measured Whole-exome sequencing and mice were randomized to treatment groups (15 mice Genomic DNA (gDNA) was isolated using the Pure- each). The next day (day 1) treatments began as follows: Link Genomic DNA Mini Kit (Life Technologies). Whole- lapatinib (48 mg/kg; GlaxoSmithKline and LC Laborato- exome sequencing performed by Otogenetics Corpora- ries), BYL719 (48mg/kg; Novartis), the combination of tion using NimbleGen V2 exome enrichment and Illumina both, or vehicle by daily oral
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