2. Academic Validation
  3. Elacestrant demonstrates strong anti-estrogenic activity in PDX models of estrogen-receptor positive endocrine-resistant and fulvestrant-resistant breast cancer

Elacestrant demonstrates strong anti-estrogenic activity in PDX models of estrogen-receptor positive endocrine-resistant and fulvestrant-resistant breast cancer

  • NPJ Breast Cancer. 2022 Nov 29;8(1):125. doi: 10.1038/s41523-022-00483-1.
Sunil Pancholi 1,  Nikiana Simigdala 1,  Ricardo Ribas 1,  Eugene Schuster 1,  Mariana Ferreira Leal 1,  Joanna Nikitorowicz-Buniak 1,  Camilla Rega 1,  Teeru Bihani 2,  Hitisha Patel 2,  Stephen R Johnston 3,  Mitch Dowsett 4,  Lesley-Ann Martin 5
Affiliations

Affiliations

  • 1 Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, SW7 3RP, UK.
  • 2 Radius Health, Waltham, Massachusetts, MA, 02451, USA.
  • 3 Breast Unit, Royal Marsden Hospital, London, SW3 6JJ, UK.
  • 4 Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital, London, SW3 6JJ, UK.
  • 5 Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, SW7 3RP, UK. lesley-ann.martin@icr.ac.uk.
PMID: 36446866 DOI: 10.1038/s41523-022-00483-1
Abstract

The selective oestrogen receptor (ER) degrader (SERD), fulvestrant, is limited in its use for the treatment of breast Cancer (BC) by its poor oral bioavailability. Comparison of the orally bioavailable investigational SERD elacestrant, versus fulvestrant, demonstrates both drugs impact tumour growth of ER+ patient-derived xenograft models harbouring several ESR1 mutations but that elacestrant is active after acquired resistance to fulvestrant. In cell line models of endocrine sensitive and resistant breast Cancer both drugs impact the ER-cistrome, ER-interactome and transcription of oestrogen-regulated genes similarly, confirming the anti-oestrogenic activity of elacestrant. The addition of elacestrant to CDK4/6 inhibitors enhances the antiproliferative effect compared to monotherapy. Furthermore, elacestrant inhibits the growth of palbociclib-resistant cells. Lastly, resistance to elacestrant involves Type-I and Type-II Receptor Tyrosine Kinases which are amenable to therapeutic targeting. Our data support the wider clinical testing of elacestrant.

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