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

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

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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