Daily or weekly dosing with EGFR inhibitors, gefitinib and lapatinib, and AKt inhibitor MK2206 in mammary cancer models Corrigendum in /10.3892/or.2018.6802

Lubet,Ronald  A.; Steele,Vernon  E.; Juliana,M. M.; Bode,Ann; Moeinpour,Fariba; Grubbs,Clinton  J.

doi:10.3892/or.2018.6313

Daily or weekly dosing with EGFR inhibitors, gefitinib and lapatinib, and AKt inhibitor MK2206 in mammary cancer models

Corrigendum in: /10.3892/or.2018.6802

Authors:
- Ronald A. Lubet
- Vernon E. Steele
- M. M. Juliana
- Ann Bode
- Fariba Moeinpour
- Clinton J. Grubbs
View Affiliations

Affiliations: Division of Cancer Prevention, National Cancer Institute, Bethesda, MD 20852, USA, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA, Division of Cancer Biomarkers and Drug Resistance, University of Minnesota Hormel Institute, Austin, MN 55912, USA
Published online on: March 14, 2018 https://doi.org/10.3892/or.2018.6313
Pages: 1545-1553

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Daily vs. weekly dosing with EGFR inhibitors (gefitinib and lapatinib) and an AKT inhibitor (MK2206) were compared in two rodent breast cancer models. Female Sprague-Dawley rats were administered methylnitrosourea (MNU) at 50 days of age, and gefitinib (daily/weekly dosing at 10/70 mg/kg BW) or lapatinib (daily/weekly dosing at 75/525 mg/kg BW) were administered by gavage beginning 5 days after MNU. For the prevention studies, weekly or daily dosing with gefitinib or lapatinib reduced cancer multiplicity >75%, and all treatments reduced tumor weights by >90%. For the therapeutic studies, MNU-treated rats were followed until small palpable mammary cancers developed. The rats were then treated daily or weekly as above for 6 weeks. Either daily or weekly dosing with lapatinib or gefitinib caused regression in >50% of the tumors. Immunohistochemistry biomarker studies in palpable mammary cancers following a weekly dose of gefitinib showed that 1 day (but not 7 days) after treatment, the levels of phosphorylated EGFR1 were significantly decreased. In an ER-negative (ER-) Neu-overexpressing model employing MMTV-Neu/P53KO mice, daily (100 mg/kg BW/day, 5 days each week), or weekly dosing (500 or 250 mg/kg BW) with gefitinib reduced tumor multiplicity 65, 85 and 75%, respectively. In the MNU prevention model, daily dosing (100 mg/kg BW/day) with the allosteric AKT inhibitor MK2206 was ineffective, while weekly dosing (700 mg/kg BW) reduced the final tumor weight >70%. Combining weekly MK2206 with the aromatase inhibitor vorozole (0.12 mg/kg BW/day) showed that each compound alone reduced tumor multiplicity 40-50%. The combination reduced cancer multiplicity ~70%. These studies demonstrate the efficacy of weekly dosing with various protein kinase inhibitors; raising the possibility of employing these agents in a breast cancer preventive setting.

View Figures

View References

1	Salamone DS, Brandt R, Ciardiello F and Normanno N: Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol. 19:183–232. 1995. View Article : Google Scholar : PubMed/NCBI
2	Arteaga CT: Overview of epidermal growth factor receptor biology and its role as therapeutic target in human neoplasia. Semin Oncol. 29 5 Suppl 14:S3–S9. 2002. View Article : Google Scholar
3	Moasser MM and Krop IE: The evolving landscape of HER2 targeting in breast cancer. JAMA Oncol. 1:1154–1161. 2015. View Article : Google Scholar : PubMed/NCBI
4	Hida L, Ogawa S, Park JC, Park JY, Shimazu J, Horio Y and Yoshida K: Gefitinib for the treatment of non small cell lung cancer. Expert Rev Anticancer Ther. 9:17–35. 2006. View Article : Google Scholar
5	Wong SF: Cetuximab: An epidermal factor receptor monoclonal antibody for treatment of colorectal cancer. Clin Ther. 27:684–694. 2005. View Article : Google Scholar : PubMed/NCBI
6	Tan WL and Ng QS: The continuing role of epidermal growth factor receptor tyrosine kinase inhibitors in advanced squamous cell carcinoma of the lung. Transl Lung Cancer Res. 5:106–109. 2016.PubMed/NCBI
7	Polychronis A, Sinnett HD, Hadjiminas D, Singhal H, Masnsi JL, Shivapatham D, Shousha S, Jiang J, Peston D, Barrett N, et al: Preoperative gefitinib versus gefitinib and anastrozole in postmenopausal patients with oestrogen-receptor positive and epidermal-growth-factor-receptor-positive primary breast cancer: A double blind placebo controlled phase II randomized trial. Lancet Oncol. 6:383–391. 2005. View Article : Google Scholar : PubMed/NCBI
8	Baselga J, Albanell J, Ruiz A, Lluch A, Gascon P, Guillém V, González S, Sauleda S, Marimón I, Tabernero JM, et al: Phase II and tumor pharmacodynamic study of gefitinib in patients with advanced breast cancer. J Clin Oncol. 23:5323–5333. 2005. View Article : Google Scholar : PubMed/NCBI
9	Massarweh S, Thann YL, Huang J, Sexton K, Weiss H, Tsimelzon A, Beyer A, Rimawi M, Cai WY, Hilsenbeck S, et al: A phase II neoadjvant trial of anastrozole, fulvestrant, and gefitinib in patients with newly diagnosed estrogen receptor positive breast cancer. Breast Cancer Res Treat. 129:819–827. 2011. View Article : Google Scholar : PubMed/NCBI
10	Lubet RA, Szabo E, Iwata KK, Gill SC, Tucker C, Bode A, Steele VE, Juliana MM, Nicastro HL and Grubbs CJ: Effect of intermittent dosing regimens of erlotinib on methylnitrosourea-induced mammary carcinogenesis. Cancer Prev Res. 6:448–454. 2013. View Article : Google Scholar
11	Lubet RA, Szabo E, Christov K, Bode AM, Ericson ME, Steele VE, Juliana MM and Grubbs CJ: Effects of gefitinib (Iressa) on mammary cancers: Preventive studies with varied dosages, combinations with vorozole or targretin, and biomarker changes. Mol Cancer Ther. 7:972–979. 2008. View Article : Google Scholar : PubMed/NCBI
12	Li J, Cho YY, Langfald A, Carper A, Lubet RA, Grubbs CJ, Ericson ME and Bode AM: Lapatinib, a preventive/therapeutic agent against mammary cancer, suppresses RTK-mediated signaling through multiple signaling pathways. Cancer Prev Res. 4:1190–1197. 2011. View Article : Google Scholar
13	Ma CX, Sanchez C, Gao F, Crowder R, Naughton M, Pluard T, Creekmore A, Guo Z, Hoog J, Lockhart AC, et al: A Phase I Study of the AKT inhibitor MK-2206 in combination with hormonal therapy in postmenopausal women with estrogen receptor-positive metastatic breast cancer. Clin Cancer Res. 22:2650–2658. 2016. View Article : Google Scholar : PubMed/NCBI
14	Grubbs CJ, Peckham JC and McDonnough KD: Effect of ovarian hormones on the induction of 1-methyl-1nitrosourea induced mammary cancer. Carcinogenesis. 4:495–497. 1983. View Article : Google Scholar : PubMed/NCBI
15	Chan MM, Lu X, Merchant FM, Inglehart JD and Miron PL: Gene expression profiling of NMU-induced rat mammary tumors: Cross species comparison with human breast cancer. Carcinogenesis. 26:1343–1353. 2005. View Article : Google Scholar : PubMed/NCBI
16	Gottardis MM and Jordan VC: Antitumor actions of keoxifene and tamoxifen in the N-nitrosomethylurea-induced rat mammary carcinoma model. Cancer Res. 47:4020–4024. 1987.PubMed/NCBI
17	Lubet RA, Steele VE, Casebolt TL, Eto I, Kelloff GJ and Grubbs CJ: Chemopreventive effects of the aromatase inhibitors vorozole (R-83842) and 4-hydroxyandrostenedione in the methylnitrosourea (MNU)-induced mammary tumor model in Sprague-Dawley rats. Carcinogenesis. 15:2775–2780. 1994. View Article : Google Scholar : PubMed/NCBI
18	Muller WJ, Sinn E, Pattengale PK, Wallace R and Leder P: Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activiated c-neu oncogene. Cell. 54:105–115. 1988. View Article : Google Scholar : PubMed/NCBI
19	Lu C, Speers C, Zhang Y, Xu X, Hill J, Steinbis E, Celestino J, Shen Q, Kim H, Hilsenbeck S, et al: Effect of epidermal growth factor receptor inhibitor on development of estrogen receptor-negative mammary tumors. J Natl Cancer Inst. 95:1825–1833. 2003. View Article : Google Scholar : PubMed/NCBI
20	Zelazny E, Li B, Anagnostopoulos AM, Coleman A and Perkins AS: Cooperating oncogenic events in murine mammary tumorigenesis: Assessment of ErbB2, mutant p53, and mouse mammary tumor virus. Exp Mol Pathol. 70:183–193. 2001. View Article : Google Scholar : PubMed/NCBI
21	Guttman-Yassky E, Mita A, De Jonge M, Matthews L, McCarthy S, Iwata KK, Verweij J, Rowinsky EK and Krueger JG: Characterization of the cutaneous pathology in (NSCLC) patients treated with (EGFR) tyrosine kinase inhibitor erlotinib. Eur J Cancer. 46:2010–2019. 2010. View Article : Google Scholar : PubMed/NCBI
22	Christov K, Shilkaitis A, Green A, Mehta RG, Grubbs C, Kelloff G and Lubet R: Cellular responses of mammary carcinomas to aromatase inhibitors: Effects of vorozole. Breast Cancer Res Treat. 60:117–128. 2000. View Article : Google Scholar : PubMed/NCBI
23	Lubet RA, Boring D, Steele VE, Ruppert JM, Juliana MM and Grubbs CJ: Lack of efficacy of the statins atorvastatin and lovastatin in rodent mammary carcinogenesis. Cancer Prev Res. 2:161–167. 2009. View Article : Google Scholar
24	Dowsett M, Smith IE, Ebbs SR, Dixon JM, Skene A, Griffith C, Boeddinghaus I, Salter J, Detre S, Hills M, et al: Short-term changes in Ki-67 during neoadjuvant treatment of primary breast cancer with anastrozole or tamoxifen alone or combined correlate with recurrence-free survival. Clin Cancer Res. 11:951S–958S. 2005.PubMed/NCBI
25	Grommes C, Oxnard GR, Kris MG, Miller VA, Pao W, Holodny AI, Clarke JL and Lassman AB: ‘Pulsatile’ high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol. 13:1364–1369. 2011. View Article : Google Scholar : PubMed/NCBI
26	Milton DT, Azzoli CG, Heelan RT, Venkatraman EM, Gomez JE, Kris MG, Krug LM, Pao W, Rizvi NA, Dunne M and Miller VA: A phase I/II study of weekly high-dose erlotinib in previously treated patients with nonsmall cell lung cancer. Cancer. 107:1034–1041. 2006. View Article : Google Scholar : PubMed/NCBI
27	Samadder NJ, Neklason DW, Boucher KM, Byrne KR, Kanth P, Samowitz W, Jones D, Tavtigian SV, Done MW, Berry T, et al: Effects of Sulindac and erlotinib vs placebo on duodenal neoplasia in familial adenomatous polyposis: A randomized clinical trial. JAMA. 315:1266–1275. 2016. View Article : Google Scholar : PubMed/NCBI
28	Chandarlapaty S, Sawai A, Scaltriti M, Rodrik-Outmezguine V, Grbovic-Huezo O, Serra V, Majumder PK, Baselga J and Rosen N: AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell. 19:58–71. 2011. View Article : Google Scholar : PubMed/NCBI
29	Ercan D, Xu C, Yanaita M, Monast CS, Pratilas CA, Montero J, Butaney M, Shimamura T, Sholl L, Ivanova EV, et al: Reactivation of ERK signaling causes resistance to EGFR kinase inhibitors. Cancer Discov. 2:934–947. 2012. View Article : Google Scholar : PubMed/NCBI
30	Yang W, Hosford SR, Dillon LM, Shee K, Liu SC, Bean JR, Salphati L, Pang J, Zhang X, Nannini MA, et al: Strategically timing inhibition of phosphatidylinositol 3-kinase to maximize therapeutic index in estrogen receptor alpha-positive PIK3CA-mutant breast cancer. Clin Cancer Res. 22:2250–2260. 2016. View Article : Google Scholar : PubMed/NCBI
31	Zhang Q, Li R, Chen X, Lee SB, Pan J, Xiong D, Hu J, Miller MS, Szabo E, Lubet RA, et al: Effects of weekly or daily dosing regimen of Gefitinib in mouse models of lung cancer. Oncotarget. 8:72447–72456. 2017.PubMed/NCBI