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BMC Cancer
Published in: BMC Cancer 1/2017

Open Access 01-12-2017 | Research article

Inhibition of PI3K-AKT-mTOR pathway sensitizes endometrial cancer cell lines to PARP inhibitors

Authors: Charles-André Philip, Ido Laskov, Marie-Claude Beauchamp, Maud Marques, Oreekha Amin, Joanna Bitharas, Roy Kessous, Liron Kogan, Tahira Baloch, Walter H. Gotlieb, Amber Yasmeen

Published in: BMC Cancer | Issue 1/2017

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Abstract

Background

Phosphatase and Tensin homolog (PTEN) is a tumor suppressor gene. Loss of its function is the most frequent genetic alteration in endometrioid endometrial cancers (70–80%) and high grade tumors (90%). We assessed the sensitivity of endometrial cancer cell lines to PARP inhibitors (olaparib and BMN-673) and a PI3K inhibitor (BKM-120), alone or in combination, in the context of their PTEN mutation status. We also highlighted a direct pathway linking PTEN to DNA repair.

Methods

Using endometrial cancer cellular models with known PTEN status, we evaluated their homologous recombination (HR) functionality by RAD51 foci formation assay. The 50% Inhibitory concentration (IC50) of PI3K and PARP inhibitors in these cells was assessed, and western blotting was performed to determine the expression of proteins involved in the PI3K/mTOR pathway. Moreover, we explored the interaction between RAD51 and PI3K/mTOR by immunofluorescence. Next, the combination effect of PI3K and PARP inhibitors on cell proliferation was evaluated by a clonogenic assay.

Results

Cells with mutated PTEN showed over-activation of the PI3K/mTOR pathway. These cells were more sensitive to PARP inhibition compared to PTEN wild-type cells. In addition, PI3K inhibitor treatment reduced RAD51 foci formation in PTEN mutated cells, and sensitized these cells to PARP inhibitor.

Conclusion

Targeting both PARP and PI3K might lead to improved personalized therapeutic approaches in endometrial cancer patients with PTEN mutations. Understanding the complex interaction of PTEN mutations with DNA repair in endometrial cancer will help to better select patients that are likely to respond to some of the new and costly targeted therapies.
Literature
1.
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86.CrossRefPubMed
2.
Wartko P, Sherman ME, Yang HP, Felix AS, Brinton LA, Trabert B. Recent changes in endometrial cancer trends among menopausal-age US women. Cancer Epidemiol. 2013;37(4):374–7.CrossRefPubMedPubMedCentral
3.
Creasman WT, Odicino F, Maisonneuve P, Quinn MA, Beller U, Benedet JL, et al. Carcinoma of the corpus uteri. FIGO 26th annual report on the results of treatment in gynecological cancer. Int J Gynaecol Obstet. 2006;95(Suppl 1):S105–43.CrossRefPubMed
4.
Kong A, Johnson N, Kitchener HC, Lawrie TA. Adjuvant radiotherapy for stage I endometrial cancer: an updated Cochrane systematic review and meta-analysis. J Natl Cancer Inst. 2012;104(21):1625–34.CrossRefPubMed
5.
Stelloo E, Nout RA, Osse EM, Jurgenliemk-Schulz IJ, Jobsen JJ, Lutgens LC, et al. Improved risk assessment by integrating molecular and Clinicopathological factors in early-stage endometrial cancer-combined analysis of the PORTEC cohorts. Clin Cancer Res. 2016;22(16):4215–24.CrossRefPubMed
6.
Murali R, Soslow RA, Weigelt B. Classification of endometrial carcinoma: more than two types. Lancet Oncol. 2014;15(7):e268–78.CrossRefPubMed
7.
Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, et al. PTEN, a putative protein tyrosine Phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997;275(5308):1943–7.CrossRefPubMed
8.
Steck PA, Pershouse MA, Jasser SA, Yung WKA, Lin H, Ligon AH, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 That is mutated in multiple advanced cancers. Nat Genet. 1997;15(4):356–62.CrossRefPubMed
9.
Xu W, Yang Z, Zhou S-F, Lu N. Posttranslational regulation of phosphatase and tensin homolog (PTEN) and its functional impact on cancer behaviors. Drug Des Devel Ther. 2014;8:1745–51.CrossRefPubMedPubMedCentral
10.
11.
12.
Akiyama-Abe A, Minaguchi T, Nakamura Y, Michikami H, Shikama A, Nakao S et al. Loss of PTEN expression is an independent predictor of favourable survival in endometrial carcinomas. Br J Cancer. 2013;109(6):1703-10. doi:10.​1038/​bjc.​2013.​455.
13.
Kumar A, Fernandez-Capetillo O, Carrera AC. Nuclear phosphoinositide 3-kinase β controls double-strand break DNA repair. Proc Natl Acad Sci U S A. 2010;107(16):7491–6.CrossRefPubMedPubMedCentral
14.
Ibrahim YH, Garcia-Garcia C, Serra V, He L, Torres-Lockhart K, Prat A, et al. PI3K Inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. Cancer discovery. 2012;2(11):1036–47.CrossRefPubMedPubMedCentral
15.
Satoh MS, Lindahl T. Role of poly(ADP-ribose) formation in DNA repair. Nature. 1992;356(6367):356–8.CrossRefPubMed
16.
Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917–21.CrossRefPubMed
17.
Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434(7035):913–7.CrossRefPubMed
18.
Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn KM, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet. 2010;376(9737):245–51.CrossRefPubMed
19.
Gelmon KA, Tischkowitz M, Mackay H, Swenerton K, Robidoux A, Tonkin K, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 2011;12(9):852–61.CrossRefPubMed
20.
Amin O, Beauchamp MC, Nader PA, Laskov I, Iqbal S, Philip CA, et al. Suppression of homologous recombination by insulin-like growth factor-1 inhibition sensitizes cancer cells to PARP inhibitors. BMC Cancer. 2015;15:817.CrossRefPubMedPubMedCentral
21.
Koppensteiner R, Samartzis EP, Noske A, von Teichman A, Dedes I, Gwerder M, et al. Effect of MRE11 loss on PARP-inhibitor sensitivity in endometrial cancer in vitro. PLoS One. 2014;9(6):e100041.CrossRefPubMedPubMedCentral
22.
Shen Y, Rehman FL, Feng Y, Boshuizen J, Bajrami I, Elliott R, et al. BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency. Clinical Cancer Res. 2013;19(18):5003–15.CrossRef
23.
Alvarez RD, Matulonis UA, Herzog TJ, Coleman RL, Monk BJ, Markman M. Moving beyond the platinum sensitive/resistant paradigm for patients with recurrent ovarian cancer. Gynecol Oncol. 2016;141(3):405–9.CrossRefPubMed
24.
Mendes-Pereira AM, Martin SA, Brough R, McCarthy A, Taylor JR, Kim JS, et al. Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol Med. 2009;1(6–7):315–22.CrossRefPubMedPubMedCentral
25.
Gonzalez-Billalabeitia E, Seitzer N, Song SJ, Song MS, Patnaik A, Liu XS, et al. Vulnerabilities of PTEN-TP53-deficient prostate cancers to compound PARP-PI3K inhibition. Cancer discovery. 2014;4(8):896–904.CrossRefPubMedPubMedCentral
26.
Chatterjee P, Choudhary GS, Sharma A, Singh K, Heston WD, Ciezki J, et al. PARP inhibition sensitizes to low dose-rate radiation TMPRSS2-ERG fusion gene-expressing and PTEN-deficient prostate cancer cells. PLoS One. 2013;8(4):e60408.CrossRefPubMedPubMedCentral
27.
McEllin B, Camacho CV, Mukherjee B, Hahm B, Tomimatsu N, Bachoo RM, et al. PTEN loss compromises homologous recombination repair in astrocytes: implications for glioblastoma therapy with temozolomide or poly(ADP-ribose) polymerase inhibitors. Cancer Res. 2010;70(13):5457–64.CrossRefPubMedPubMedCentral
28.
Minami D, Takigawa N, Takeda H, Takata M, Ochi N, Ichihara E, et al. Synergistic effect of olaparib with combination of cisplatin on PTEN-deficient lung cancer cells. Mol Cancer Res. 2013;11(2):140–8.CrossRefPubMed
29.
Dedes KJ, Wetterskog D, Mendes-Pereira AM, Natrajan R, Lambros MB, Geyer FC, et al. PTEN deficiency in Endometrioid endometrial Adenocarcinomas predicts sensitivity to PARP inhibitors. Sci Transl Med. 2010;2(53):53ra75.CrossRefPubMed
30.
31.
Dillon LM, Miller TW. Therapeutic targeting of cancers with loss of PTEN function. Curr Drug Targets. 2014;15(1):65–79.
32.
Maira SM, Pecchi S, Huang A, Burger M, Knapp M, Sterker D, et al. Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol Cancer Ther. 2012;11(2):317–28.CrossRefPubMed
33.
Bendell JC, Rodon J, Burris HA, de Jonge M, Verweij J, Birle D, et al. Phase I, dose-escalation study of BKM120, an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2012;30(3):282–90.CrossRefPubMed
34.
Vansteenkiste JF, Canon JL, Braud FD, Grossi F, De Pas T, Gray JE, et al. Safety and efficacy of Buparlisib (BKM120) in patients with PI3K pathway-activated non-small cell lung cancer: results from the phase II BASALT-1 study. J Thorac Oncol. 2015;10(9):1319–27.CrossRefPubMedPubMedCentral
35.
Hyman DM, Snyder AE, Carvajal RD, Gerecitano JF, Voss MH, Ho AL, et al. Parallel phase Ib studies of two schedules of buparlisib (BKM120) plus carboplatin and paclitaxel (q21 days or q28 days) for patients with advanced solid tumors. Cancer Chemother Pharmacol. 2015;75(4):747–55.CrossRefPubMed
36.
Bedard PL, Tabernero J, Janku F, Wainberg ZA, Paz-Ares L, Vansteenkiste J, et al. A phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors. Clin Cancer Res. 2015;21(4):730–8.CrossRefPubMed
37.
Bradford LS, Rauh-Hain A, Clark RM, Groeneweg JW, Zhang L, Borger D, et al. Assessing the efficacy of targeting the phosphatidylinositol 3-kinase/AKT/mTOR signaling pathway in endometrial cancer. Gynecol Oncol. 2014;133(2):346–52.CrossRefPubMed
38.
Kuramoto H, Tamura S, Notake Y. Establishment of a cell line of human endometrial adenocarcinoma in vitro. Am J Obstet Gynecol. 1972;114(8):1012–9.CrossRefPubMed
39.
Xiong S, Klausen C, Cheng JC, Leung PC. Activin B promotes endometrial cancer cell migration by down-regulating E-cadherin via SMAD-independent MEK-ERK1/2-SNAIL signaling. Oncotarget. 2016;7(26):40060–72.CrossRefPubMedPubMedCentral
40.
Albitar L, Pickett G, Morgan M, Davies S, Leslie KK. Models representing type I and type II human endometrial cancers: Ishikawa H and Hec50co cells. Gynecol Oncol. 2007;106(1):52–64.CrossRefPubMed
41.
Chen S, Sun KX, Liu BL, Zong ZH, Zhao Y. MicroRNA-505 functions as a tumor suppressor in endometrial cancer by targeting TGF-alpha. Mol Cancer. 2016;15:11.CrossRefPubMedPubMedCentral
42.
Nishida M, Kasahara K, Kaneko M, Iwasaki H, Hayashi K. Establishment of a new human endometrial adenocarcinoma cell line, Ishikawa cells, containing estrogen and progesterone receptors. Nihon Sanka Fujinka Gakkai zasshi. 1985;37(7):1103–11.PubMed
43.
Miyasaka A, Oda K, Ikeda Y, Wada-Hiraike O, Kashiyama T, Enomoto A, et al. Anti-tumor activity of olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, in cultured endometrial carcinoma cells. BMC Cancer. 2014;14:179.CrossRefPubMedPubMedCentral
44.
Oda K, Stokoe D, Taketani Y, McCormick F. High frequency of coexistent mutations of PIK3CA and PTEN genes in endometrial carcinoma. Cancer Res. 2005;65(23):10669–73.CrossRefPubMed
45.
Dawe CJ, Banfield WG, Morgan WD, Slatick MS, Curth HO. Growth in continuos culture, and in hamsters, of cells from a neoplasm associated with Acanthosis Nigricans. J Natl Cancer Inst. 1964;33:441–56.PubMed
46.
Chiappinelli KB, Haynes BC, Brent MR, Goodfellow PJ. Reduced DICER1 elicits an interferon response in endometrial cancer cells. Mol Cancer Res. 2012;10(3):316–25.CrossRefPubMedPubMedCentral
47.
Korch C, Spillman MA, Jackson TA, Jacobsen BM, Murphy SK, Lessey BA, et al. DNA profiling analysis of endometrial and ovarian cell lines reveals misidentification, redundancy and contamination. Gynecol Oncol. 2012;127(1):241–8.CrossRefPubMedPubMedCentral
48.
Weigelt B, Warne PH, Lambros MB, Reis-Filho JS, Downward J. PI3K pathway dependencies in endometrioid endometrial cancer cell lines. Clin Cancer Res. 2013;19(13):3533–44. doi:10.​1158/​1078-0432.​CCR-12-3815.
49.
Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361(2):123–34.CrossRefPubMed
50.
Ando Y, Inada-Inoue M, Mitsuma A, Yoshino T, Ohtsu A, Suenaga N, et al. Phase I dose-escalation study of buparlisib (BKM120), an oral pan-class I PI3K inhibitor, in Japanese patients with advanced solid tumors. Cancer Sci. 2014;105(3):347–53.CrossRefPubMedPubMedCentral
51.
Franken NA, Rodermond HM, Stap J, Haveman J, van Bree C. Clonogenic assay of cells in vitro. Nat Protoc. 2006;1(5):2315–9.CrossRefPubMed
52.
Maor S, Papa MZ, Yarden RI, Friedman E, Lerenthal Y, Lee SW, et al. Insulin-like growth factor-I controls BRCA1 gene expression through activation of transcription factor Sp1. Horm Metab Res. 2007;39(3):179–85.CrossRefPubMed
53.
Laskov I, Abou-Nader P, Amin O, Philip CA, Beauchamp MC, Yasmeen A, et al. Metformin increases E-cadherin in tumors of diabetic patients with endometrial cancer and suppresses epithelial-Mesenchymal transition in endometrial cancer cell lines. Int J Gynecol Cancer. 2016;26(7):1213–21.CrossRefPubMed
54.
Xiong S, Cheng JC, Klausen C, Zhao J, Leung PC. TGF-beta1 stimulates migration of type II endometrial cancer cells by down-regulating PTEN via activation of SMAD and ERK1/2 signaling pathways. Oncotarget. 2016;7(38):61262–72. doi:10.​18632/​oncotarget.​11311.
55.
Tsikouras P, Bouchlariotou S, Vrachnis N, Dafopoulos A, Galazios G, Csorba R et al. Endometrial cancer: molecular and therapeutic aspects. Eur J Obstet Gynecol Reprod Biol. 2013;169(1):1–9. doi:10.​1016/​j.​ejogrb.​2013.​01.​018.
56.
Hers I, Vincent EE, Tavaré JM. Akt signalling in health and disease. Cell Signal. 2011;23(10):1515–27.CrossRefPubMed
57.
Laskov I, Drudi L, Beauchamp MC, Yasmeen A, Ferenczy A, Pollak M, et al. Anti-diabetic doses of metformin decrease proliferation markers in tumors of patients with endometrial cancer. Gynecol Oncol. 2014;134(3):607–14.CrossRefPubMed
58.
Janzen DM, Paik DY, Rosales MA, Yep B, Cheng D, Witte ON, et al. Low levels of circulating estrogen sensitize PTEN-null endometrial tumors to PARP inhibition in vivo. Mol Cancer Ther. 2013;12(12):2917–28.CrossRefPubMedPubMedCentral
59.
Juvekar A, Burga LN, Hu H, Lunsford EP, Ibrahim YH, Balmana J, et al. Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer. Cancer discovery. 2012;2(11):1048–63.CrossRefPubMedPubMedCentral
60.
Cardnell RJ, Feng Y, Diao L, Fan YH, Masrorpour F, Wang J, et al. Proteomic markers of DNA repair and PI3K pathway activation predict response to the PARP inhibitor BMN 673 in small cell lung cancer. Clin Cancer Res. 2013;19(22):6322–8.CrossRefPubMed
61.
De P, Sun Y, Carlson JH, Friedman LS, Leyland-Jones BR, Dey N. Doubling down on the PI3K-AKT-mTOR pathway enhances the antitumor efficacy of PARP inhibitor in triple negative breast cancer model beyond BRCA-ness. Neoplasia. 2014;16(1):43–72.CrossRefPubMedPubMedCentral
Metadata
Title
Inhibition of PI3K-AKT-mTOR pathway sensitizes endometrial cancer cell lines to PARP inhibitors
Authors
Charles-André Philip
Ido Laskov
Marie-Claude Beauchamp
Maud Marques
Oreekha Amin
Joanna Bitharas
Roy Kessous
Liron Kogan
Tahira Baloch
Walter H. Gotlieb
Amber Yasmeen
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2017
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-017-3639-0

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