PKMYT1 is a Marker of Treatment Response and a Therapeutic Target for CDK4/6 Inhibitor-Resistance in ER+ Breast Cancer

  • Mol Cancer Ther. 2024 May 23. doi: 10.1158/1535-7163.MCT-23-0564.
Anran Chen  1 ,  Beom-Jun Kim  2 ,  Aparna Mitra  1 ,  Craig T Vollert  3 ,  Jonathan T Lei  1 ,  Diana Fandino  2 ,  Meenakshi Anurag  1 ,  Matthew V Holt  1 ,  Xuxu Gou  2 ,  Jacob B Pilcher  1 ,  Matthew P Goetz  4 ,  Donald W Northfelt  5 ,  Susan G Hilsenbeck  1 ,  C Gary Marshall  6 ,  Marc L Hyer  7 ,  Robert Papp  8 ,  Shou-Yun Yin  9 ,  Carmine De Angelis  10 ,  Rachel Schiff  1 ,  Suzanne A W Fuqua  1 ,  Cynthia X Ma  11 ,  Charles E Foulds  1 ,  Matthew J Ellis  1
Affiliations
  • 1. Baylor College of Medicine, Houston, TX, United States.
  • 2. Baylor College of Medicine, Houston, United States.
  • 3. Baylor College of Medicine, Houston, Texas, United States.
  • 4. Mayo Clinic, Rochester, MN, United States.
  • 5. Mayo Clinic, Phoenix, AZ, United States.
  • 6. Repare Therapeutics, Watertown, MA, United States.
  • 7. Repare Therapeutics, Cambridge, MA, United States.
  • 8. Repare Therapeutics, Saint Laurent, Canada.
  • 9. Repare Therapeutics, Saint-Laurent, Quebec, Canada.
  • 10. University of Naples Federico II, Naples, Italy.
  • 11. Washington University in St. Louis School of Medicine, St, Louis, MO, United States.
PMID: 38781103 DOI: 10.1158/1535-7163.MCT-23-0564
Abstract

Endocrine therapies (ET) with CDK4/6 inhibition are the standard treatment for estrogen receptor-α-positive (ER+) breast Cancer, however drug resistance is common. In this study, proteogenomic analyses of 22 ER+ breast Cancer patient-derived xenografts (PDXs) demonstrated that PKMYT1, a Wee1 homolog, is estradiol (E2) regulated in E2-dependent PDXs and constitutively expressed when growth is E2-independent. In clinical samples, high PKMYT1 mRNA levels associated with resistance to both ET and CDK4/6 inhibition. The PKMYT1 Inhibitor lunresertib (RP-6306) with gemcitabine selectively and synergistically reduced the viability of ET and palbociclib-resistant ER+ breast Cancer cells without functional p53. In vitro the combination increased DNA damage and Apoptosis. In palbociclib-resistant, TP53 mutant PDX organoids and xenografts, RP-6306 with low-dose gemcitabine induced greater tumor volume reduction compared to treatment with either single agent. Our study demonstrates the clinical potential of RP-6306 in combination with gemcitabine for ET and CDK4/6 inhibitor resistant TP53 mutant ER+ breast Cancer.

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