SAR439859, a Novel Selective Estrogen Receptor Degrader (SERD), Demonstrates Effective and Broad Antitumor Activity in Wild-Type and Mutant ER-Positive Breast Cancer Models.
Journal
Molecular cancer therapeutics
ISSN: 1538-8514
Titre abrégé: Mol Cancer Ther
Pays: United States
ID NLM: 101132535
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
08
05
2020
revised:
31
08
2020
accepted:
03
11
2020
pubmed:
15
12
2020
medline:
21
10
2021
entrez:
14
12
2020
Statut:
ppublish
Résumé
Primary treatment for estrogen receptor-positive (ER+) breast cancer is endocrine therapy. However, substantial evidence indicates a continued role for ER signaling in tumor progression. Selective estrogen receptor degraders (SERD), such as fulvestrant, induce effective ER signaling inhibition, although clinical studies with fulvestrant report insufficient blockade of ER signaling, possibly due to suboptimal pharmaceutical properties. Furthermore, activating mutations in the ER have emerged as a resistance mechanism to current endocrine therapies. New oral SERDs with improved drug properties are under clinical investigation, but the biological profile that could translate to improved therapeutic benefit remains unclear. Here, we describe the discovery of SAR439859, a novel, orally bioavailable SERD with potent antagonist and degradation activities against both wild-type and mutant Y537S ER. Driven by its fluoropropyl pyrrolidinyl side chain, SAR439859 has demonstrated broader and superior ER antagonist and degrader activities across a large panel of ER+ cells, compared with other SERDs characterized by a cinnamic acid side chain, including improved inhibition of ER signaling and tumor cell growth. Similarly,
Identifiants
pubmed: 33310762
pii: 1535-7163.MCT-20-0390
doi: 10.1158/1535-7163.MCT-20-0390
doi:
Substances chimiques
Receptors, Estrogen
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
250-262Informations de copyright
©2020 American Association for Cancer Research.
Références
Davies C, Godwin J, Gray R, Clarke M, Cutter D, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378:771–84.
Cuzick J, Sestak I, Baum M, Buzdar A, Howell A, Dowsett M, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol. 2010;11:1135–41.
Aihara T, Yokota I, Hozumi Y, Aogi K, Iwata H, Tamura M, et al. Anastrozole versus tamoxifen as adjuvant therapy for Japanese postmenopausal patients with hormone-responsive breast cancer: efficacy results of long-term follow-up data from the N-SAS BC 03 trial. Breast Cancer Res Treat. 2014;148:337–43.
Dowsett M, Cuzick J, Ingle J, Coates A, Forbes J, Bliss J, et al. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol. 2010;28:509–18.
Chia S, Gradishar W, Mauriac L, Bines J, Amant F, Federico M, et al. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol. 2008;26:1664–70.
Mauri D, Pavlidis N, Polyzos NP, Ioannidis JP. Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: meta-analysis. J Natl Cancer Inst. 2006;98:1285–91.
Jeselsohn R, Yelensky R, Buchwalter G, Frampton G, Meric-Bernstam F, Gonzalez-Angulo AM, et al. Emergence of constitutively active estrogen receptor-alpha mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res. 2014;20:1757–67.
Merenbakh-Lamin K, Ben-Baruch N, Yeheskel A, Dvir A, Soussan-Gutman L, Jeselsohn R, et al. D538G mutation in estrogen receptor-alpha: a novel mechanism for acquired endocrine resistance in breast cancer. Cancer Res. 2013;73:6856–64.
Robinson DR, Wu YM, Vats P, Su F, Lonigro RJ, Cao X, et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet. 2013;45:1446–51.
Toy W, Shen Y, Won H, Green B, Sakr RA, Will M, et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet. 2013;45:1439–45.
Flanagan JJ, Neklesa TK. Targeting nuclear receptors with PROTAC degraders. Mol Cell Endocrinol. 2019;493:110452.
McDonnell DP. The molecular pharmacology of estrogen receptor modulators: implications for the treatment of breast cancer. Clin Cancer Res. 2005;11:871s–7s.
Shah YM, Rowan BG. The Src kinase pathway promotes tamoxifen agonist action in Ishikawa endometrial cells through phosphorylation-dependent stabilization of estrogen receptor (alpha) promoter interaction and elevated steroid receptor coactivator 1 activity. Mol Endocrinol. 2005;19:732–48.
Viedma-Rodriguez R, Baiza-Gutman L, Salamanca-Gomez F, Diaz-Zaragoza M, Martinez-Hernandez G, Ruiz Esparza-Garrido R, et al. Mechanisms associated with resistance to tamoxifen in estrogen receptor-positive breast cancer (review). Oncol Rep. 2014;32:3–15.
de Leeuw R, Neefjes J, Michalides R. A role for estrogen receptor phosphorylation in the resistance to tamoxifen. Int J Breast Cancer. 2011;2011:232435.
Kojetin DJ, Burris TP, Jensen EV, Khan SA. Implications of the binding of tamoxifen to the coactivator recognition site of the estrogen receptor. Endocr Relat Cancer. 2008;15:851–70.
Fanning SW, Mayne CG, Dharmarajan V, Carlson KE, Martin TA, Novick SJ, et al. Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation. Elife. 2016;5:e12792.
Toy W, Weir H, Razavi P, Lawson M, Goeppert AU, Mazzola AM, et al. Activating ESR1 mutations differentially affect the efficacy of ER antagonists. Cancer Discov. 2017;7:277–87.
Katzenellenbogen JA, Mayne CG, Katzenellenbogen BS, Greene GL, Chandarlapaty S. Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance. Nat Rev Cancer. 2018;18:377–88.
Faslodex (fulvestrant) injection. 2011.
Perey L, Paridaens R, Hawle H, Zaman K, Nole F, Wildiers H, et al. Clinical benefit of fulvestrant in postmenopausal women with advanced breast cancer and primary or acquired resistance to aromatase inhibitors: final results of phase II Swiss Group for clinical cancer research trial (SAKK 21/00). Ann Oncol. 2007;18:64–9.
McDonnell DP, Chang CY, Norris JD. Capitalizing on the complexities of estrogen receptor pharmacology in the quest for the perfect SERM. Ann N Y Acad Sci. 2001;949:16–35.
Wijayaratne AL, Nagel SC, Paige LA, Christensen DJ, Norris JD, Fowlkes DM, et al. Comparative analyses of mechanistic differences among antiestrogens. Endocrinology. 1999;140:5828–40.
Robertson JFR, Jiang Z, Di Leo A, Ohno S, Pritchard KI, Ellis M, et al. A meta-analysis of clinical benefit rates for fulvestrant 500 mg vs. alternative endocrine therapies for hormone receptor-positive advanced breast cancer. Breast Cancer. 2019;26:703–11.
van Kruchten M, de Vries EG, Glaudemans AW, van Lanschot MC, van Faassen M, Kema IP, et al. Measuring residual estrogen receptor availability during fulvestrant therapy in patients with metastatic breast cancer. Cancer Discov. 2015;5:72–81.
Joseph JD, Darimont B, Zhou W, Arrazate A, Young A, Ingalla E, et al. The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer. Elife. 2016;5:e15828.
Lai A, Kahraman M, Govek S, Nagasawa J, Bonnefous C, Julien J, et al. Identification of GDC-0810 (ARN-810), an orally bioavailable selective estrogen receptor degrader (SERD) that demonstrates robust activity in tamoxifen-resistant breast cancer xenografts. J Med Chem. 2015;58:4888–904.
Weir HM, Bradbury RH, Lawson M, Rabow AA, Buttar D, Callis RJ, et al. AZD9496: an oral estrogen receptor inhibitor that blocks the growth of ER-positive and ESR1-mutant breast tumors in preclinical models. Cancer Res. 2016;76:3307–18.
Patel HK, Bihani T. Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer treatment. Pharmacol Ther. 2018;186:1–24.
Traboulsi T, El Ezzy M, Gleason JL, Mader S. Antiestrogens: structure-activity relationships and use in breast cancer treatment. J Mol Endocrinol. 2017;58:R15–R31.
Kocanova S, Mazaheri M, Caze-Subra S, Bystricky K. Ligands specify estrogen receptor alpha nuclear localization and degradation. BMC Cell Biol. 2010;11:98.
Kahraman M, Govek SP, Nagasawa JY, Lai A, Bonnefous C, Douglas K, et al. Maximizing ER-alpha degradation maximizes activity in a tamoxifen-resistant breast cancer model: identification of GDC-0927. ACS Med Chem Lett. 2019;10:50–5.
Bihani T, Patel HK, Arlt H, Tao N, Jiang H, Brown JL, et al. Elacestrant (RAD1901), a selective estrogen receptor degrader (SERD), has antitumor activity in multiple ER(+) breast cancer patient-derived xenograft models. Clin Cancer Res. 2017;23:4793–804.
Tria GS, Abrams T, Baird J, Burks HE, Firestone B, Gaither LA, et al. Discovery of LSZ102, a potent, orally bioavailable selective estrogen receptor degrader (SERD) for the treatment of estrogen receptor positive breast cancer. J Med Chem. 2018;61:2837–64.
Guan J, Zhou W, Hafner M, Blake RA, Chalouni C, Chen IP, et al. Therapeutic ligands antagonize estrogen receptor function by impairing its mobility. Cell. 2019;178:949–63.
Ethier SP, Mahacek ML, Gullick WJ, Frank TS, Weber BL. Differential isolation of normal luminal mammary epithelial cells and breast cancer cells from primary and metastatic sites using selective media. Cancer Res. 1993;53:627–35.
DeRose YS, Wang G, Lin YC, Bernard PS, Buys SS, Ebbert MT, et al. Tumor grafts derived from women with breast cancer authentically reflect tumor pathology, growth, metastasis and disease outcomes. Nat Med. 2011;17:1514–20.
Bouaboula M, Brollo M, Certal V, El-Ahmad Y, Filoche-Romme B, Halley F, et al. inventors. Novel substituted 6,7-dihydro-5H-benzo[7]annulene compounds, processes for their preparation and therapeutic uses thereof. 2017.
Smith ND, Kahraman M, Govek SP, Nagasawa JY, Lai AG, Bonnefous C, et al. Preparation of substituted 3-[4-[1-(1H-indazol-5-yl)-2-phenylvinyl]phenyl]acrylic acid and derivatives as estrogen receptor modulators. 2012.
Akhtar N, Bradbury RH, Buttar D, Currie GS, De Savi C, Donald CS, et al. Preparation of (E)-3-[4-(2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl]acrylic acid derivatives as antitumor agents. 2014.
Bouaboula M, Brollo M, Certal V, El-Ahmad Y, Filoche-Romme B, Halley F, et al. Novel substituted N-(3-fluoropropyl)-pyrrolidine compounds, processes for their preparation and therapeutic uses thereof.
Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21.
Trapnell C, Williams BA, Pertea G, Mortazavi A, Kwan G, van Baren MJ, et al. Transcript assembly and quantification by RNA-seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol. 2010;28:511–5.
Lin CY, Strom A, Vega VB, Kong SL, Yeo AL, Thomsen JS, et al. Discovery of estrogen receptor alpha target genes and response elements in breast tumor cells. Genome Biol. 2004;5:R66.
Welboren WJ, Stunnenberg HG, Sweep FC, Span PN. Identifying estrogen receptor target genes. Mol Oncol. 2007;1:138–43.
Wardell SE, Nelson ER, Chao CA, Alley HM, McDonnell DP. Evaluation of the pharmacological activities of RAD1901, a selective estrogen receptor degrader. Endocr Relat Cancer. 2015;22:713–24.
Brunner N, Frandsen TL, Holst-Hansen C, Bei M, Thompson EW, Wakeling AE, et al. MCF7/LCC2: a 4-hydroxytamoxifen resistant human breast cancer variant that retains sensitivity to the steroidal antiestrogen ICI 182,780. Cancer Res. 1993;53:3229–32.
Casa AJ, Potter AS, Malik S, Lazard Z, Kuiatse I, Kim HT, et al. Estrogen and insulin-like growth factor-I (IGF-I) independently down-regulate critical repressors of breast cancer growth. Breast Cancer Res Treat. 2012;132:61–73.
Liao GJ, Clark AS, Schubert EK, Mankoff DA. 18F-fluoroestradiol PET: current status and potential future clinical applications. J Nucl Med. 2016;57:1269–75.
Sikora MJ, Cooper KL, Bahreini A, Luthra S, Wang G, Chandran UR, et al. Invasive lobular carcinoma cell lines are characterized by unique estrogen-mediated gene expression patterns and altered tamoxifen response. Cancer Res. 2014;74:1463–74.
Ponnusamy S, Asemota S, Schwartzberg LS, Guestini F, McNamara KM, Pierobon M, et al. Androgen receptor is a non-canonical inhibitor of wild-type and mutant estrogen receptors in hormone receptor-positive breast cancers. iScience.. 2019;21:341–58.
Hanzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics. 2013;14:7.
El-Ahmad Y, Tabart M, Halley F, Certal V, Thompson F, Filoche-Romme B, et al. Discovery of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8, 9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (SAR439859), a potent and selective estrogen receptor degrader (SERD) for the treatment of estrogen-receptor-positive breast cancer. J Med Chem. 2020;63:512–28.
Wardell SE, Yllanes AP, Chao CA, Bae Y, Andreano KJ, Desautels TK, et al. Pharmacokinetic and pharmacodynamic analysis of fulvestrant in preclinical models of breast cancer to assess the importance of its estrogen receptor-alpha degrader activity in antitumor efficacy. Breast Cancer Res Treat. 2020;179:67–77.