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Somatic loss of PIK3R1 may sensitize breast cancer to inhibitors of the MAPK pathway

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Abstract

Purpose

The PI3K pathway, which includes the PI3K catalytic subunits p110α (PIK3CA) and the PI3K regulatory subunit p85α (PIK3R1), is the most frequently altered pathway in cancer. We encountered a breast cancer patient whose tumor contained a somatic alteration in PIK3R1. Some commercial sequencing platforms suggest that somatic mutations in PIK3R1 may sensitize cancers to drugs that inhibit the mammalian target of rapamycin (mTOR). However, a review of the preclinical and clinical literature did not find evidence substantiating that hypothesis. The purpose of this study was to knock out PIK3R1 in order to determine the optimal therapeutic approach for breast cancers lacking p85α.

Methods

We created an isogenic cellular system by knocking out both alleles of the PIK3R1 gene in the non-tumorigenic human breast cell line MCF-10A. Knockout cells were compared with wild-type cells by measuring growth, cellular signaling, and response to drugs.

Results

We observed hyperphosphorylation of MEK in these knockouts, which sensitized PIK3R1-null cells to a MEK inhibitor, trametinib. However, they were not sensitized to the mTOR inhibitor, everolimus.

Conclusions

Our findings suggest that breast cancers with loss of p85α may not respond to mTOR inhibition, but may be sensitive to MEK inhibition.

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References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90. https://doi.org/10.3322/caac.20107

    Article  PubMed  Google Scholar 

  2. Lauring J, Park BH, Wolff AC (2013) The phosphoinositide-3-kinase-Akt-mTOR pathway as a therapeutic target in breast cancer. J Natl Compr Canc Netw 11(6):670–678

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bachman KE, Argani P, Samuels Y, Silliman N, Ptak J, Szabo S, Konishi H, Karakas B, Blair BG, Lin C, Peters BA, Velculescu VE, Park BH (2004) The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther 3(8):772–775

    Article  CAS  PubMed  Google Scholar 

  4. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304(5670):554

    Article  CAS  PubMed  Google Scholar 

  5. Taniguchi CM, Winnay J, Kondo T, Bronson RT, Guimaraes AR, Aleman JO, Luo J, Stephanopoulos G, Weissleder R, Cantley LC, Kahn CR (2010) The phosphoinositide 3-kinase regulatory subunit p85alpha can exert tumor suppressor properties through negative regulation of growth factor signaling. Cancer Res 70(13):5305–5315. https://doi.org/10.1158/0008-5472.CAN-09-3399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cizkova M, Vacher S, Meseure D, Trassard M, Susini A, Mlcuchova D, Callens C, Rouleau E, Spyratos F, Lidereau R, Bieche I (2013) PIK3R1 underexpression is an independent prognostic marker in breast cancer. BMC Cancer 13:545. https://doi.org/10.1186/1471-2407-13-545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zhang BH, Liu J, Zhou QX, Zuo D, Wang Y (2013) Analysis of differentially expressed genes in ductal carcinoma with DNA microarray. Eur Rev Med Pharmacol Sci 17(6):758–766

    PubMed  Google Scholar 

  8. Lin Y, Yang Z, Xu A, Dong P, Huang Y, Liu H, Li F, Wang H, Xu Q, Wang Y, Sun D, Zou Y, Zou X, Wang Y, Zhang D, Liu H, Wu X, Zhang M, Fu Y, Cai Z, Liu C, Wu S (2015) PIK3R1 negatively regulates the epithelial-mesenchymal transition and stem-like phenotype of renal cancer cells through the AKT/GSK3beta/CTNNB1 signaling pathway. Sci Rep 5:8997. https://doi.org/10.1038/srep08997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chakravarty D, Gao J, Phillips S, Kundra R, Zhang H, Wang J, Rudolph JE, Yaeger R, Soumerai T, Nissan MH, Chang MT, Chandarlapaty S, Traina TA, Paik PK, Ho AL, Hantash FM, Grupe A, Baxi SS, Callahan MK, Snyder A, Chi P, Danila DC, Gounder M, Harding JJ, Hellmann MD, Iyer G, Janjigian YY, Kaley T, Levine DA, Lowery M, Omuro A, Postow MA, Rathkopf D, Shoushtari AN, Shukla N, Voss MH, Paraiso E, Zehir A, Berger MF, Taylor BS, Saltz LB, Riely GJ, Ladanyi M, Hyman DM, Baselga J, Sabbatini P, Solit DB, Schultz N (2017) OncoKB: a precision oncology knowledge base. JCO Precis Oncol 1:1–16. https://doi.org/10.1200/po.17.00011

    Article  Google Scholar 

  10. Cheung LW, Yu S, Zhang D, Li J, Ng PK, Panupinthu N, Mitra S, Ju Z, Yu Q, Liang H, Hawke DH, Lu Y, Broaddus RR, Mills GB (2014) Naturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors. Cancer Cell 26(4):479–494. https://doi.org/10.1016/j.ccell.2014.08.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wang GM, Wong HY, Konishi H, Blair BG, Abukhdeir AM, Gustin JP, Rosen DM, Denmeade SR, Rasheed Z, Matsui W, Garay JP, Mohseni M, Higgins MJ, Cidado J, Jelovac D, Croessmann S, Cochran RL, Karnan S, Konishi Y, Ota A, Hosokawa Y, Argani P, Lauring J, Park BH (2013) Single copies of mutant KRAS and mutant PIK3CA cooperate in immortalized human epithelial cells to induce tumor formation. Cancer Res 73(11):3248–3261. https://doi.org/10.1158/0008-5472.CAN-12-1578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. TCGA (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455(7216):1061–1068. https://doi.org/10.1038/nature07385

    Article  CAS  Google Scholar 

  13. Sanjana NE, Shalem O, Zhang F (2014) Improved vectors and genome-wide libraries for CRISPR screening. Nat Methods 11(8):783–784. https://doi.org/10.1038/nmeth.3047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Turturro SB, Najor MS, Ruby CE, Cobleigh MA, Abukhdeir AM (2016) Mutations in PIK3CA sensitize breast cancer cells to physiologic levels of aspirin. Breast Cancer Res Treat 156(1):33–43. https://doi.org/10.1007/s10549-016-3729-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ignatoski KM, Lapointe AJ, Radany EH, Ethier SP (1999) erbB-2 overexpression in human mammary epithelial cells confers growth factor independence. Endocrinology 140(8):3615–3622. https://doi.org/10.1210/endo.140.8.6939

    Article  CAS  PubMed  Google Scholar 

  16. Gustin JP, Karakas B, Weiss MB, Abukhdeir AM, Lauring J, Garay JP, Cosgrove D, Tamaki A, Konishi H, Konishi Y, Mohseni M, Wang G, Rosen DM, Denmeade SR, Higgins MJ, Vitolo MI, Bachman KE, Park BH (2009) Knockin of mutant PIK3CA activates multiple oncogenic pathways. Proc Natl Acad Sci USA 106(8):2835–2840

    Article  PubMed  PubMed Central  Google Scholar 

  17. Baselga J, Im SA, Iwata H, Cortes J, De Laurentiis M, Jiang Z, Arteaga CL, Jonat W, Clemons M, Ito Y, Awada A, Chia S, Jagiello-Gruszfeld A, Pistilli B, Tseng LM, Hurvitz S, Masuda N, Takahashi M, Vuylsteke P, Hachemi S, Dharan B, Di Tomaso E, Urban P, Massacesi C, Campone M (2017) Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 18(7):904–916. https://doi.org/10.1016/S1470-2045(17)30376-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cancer Genome Atlas N (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70. https://doi.org/10.1038/nature11412

    Article  CAS  Google Scholar 

  19. LoRusso PM, Krishnamurthi SS, Rinehart JJ, Nabell LM, Malburg L, Chapman PB, DePrimo SE, Bentivegna S, Wilner KD, Tan W, Ricart AD (2010) Phase I pharmacokinetic and pharmacodynamic study of the oral MAPK/ERK kinase inhibitor PD-0325901 in patients with advanced cancers. Clin Cancer Res 16(6):1924–1937. https://doi.org/10.1158/1078-0432.CCR-09-1883

    Article  CAS  PubMed  Google Scholar 

  20. Haura EB, Ricart AD, Larson TG, Stella PJ, Bazhenova L, Miller VA, Cohen RB, Eisenberg PD, Selaru P, Wilner KD, Gadgeel SM (2010) A phase II study of PD-0325901, an oral MEK inhibitor, in previously treated patients with advanced non-small cell lung cancer. Clin Cancer Res 16(8):2450–2457. https://doi.org/10.1158/1078-0432.CCR-09-1920

    Article  CAS  PubMed  Google Scholar 

  21. Boasberg PD, Redfern CH, Daniels GA, Bodkin D, Garrett CR, Ricart AD (2011) Pilot study of PD-0325901 in previously treated patients with advanced melanoma, breast cancer, and colon cancer. Cancer Chemother Pharmacol 68(2):547–552. https://doi.org/10.1007/s00280-011-1620-1

    Article  CAS  PubMed  Google Scholar 

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Disclaimer

The work herein was completed while AMA was a faculty member at Rush University. AMA is currently an employee with the U.S. Food and Drug Administration. The views and data in this publication do not reflect the opinions of The U.S. Food and Drug Administration.

Funding

This study was funded by The Brian Piccolo Cancer Research Fund and Bears Care.

Author information

Author notes

  1. Sanja B. Turturro and Matthew S. Najor have contributed equally to this work.

Authors and Affiliations

  1. Division of Hematology, Oncology, and Cell Therapy, Department of Internal Medicine, Rush University Medical Center, 1725 W. Harrison St., Chicago, IL, 60612, USA

    Sanja B. Turturro, Matthew S. Najor, Timothy Yung, Liam Portt, Abde M. Abukhdeir & Melody A. Cobleigh

  2. School of Pharmacy, Rueckert-Hartman College for Health Professions, Regis University, 3333 Regis Boulevard, H-28, Denver, CO, 80221-1099, USA

    Christopher S. Malarkey

Authors
  1. Sanja B. Turturro
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  2. Matthew S. Najor
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  3. Timothy Yung
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  4. Liam Portt
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  6. Abde M. Abukhdeir
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Corresponding author

Correspondence to Abde M. Abukhdeir.

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Turturro, S.B., Najor, M.S., Yung, T. et al. Somatic loss of PIK3R1 may sensitize breast cancer to inhibitors of the MAPK pathway. Breast Cancer Res Treat 177, 325–333 (2019). https://doi.org/10.1007/s10549-019-05320-x

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  • DOI: https://doi.org/10.1007/s10549-019-05320-x

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