2. Academic Validation
  3. Patient-derived tumor organoids with p53 mutations, and not wild-type p53, are sensitive to synergistic combination PARP inhibitor treatment

Patient-derived tumor organoids with p53 mutations, and not wild-type p53, are sensitive to synergistic combination PARP inhibitor treatment

  • bioRxiv. 2023 Jun 22:2023.06.22.544406. doi: 10.1101/2023.06.22.544406.
Florencia P Madorsky Rowdo 1,  Gu Xiao 2,  Galina F Khramtsova 3,  John Nguyen 1,  Olufunmilayo I Olopade 3,  Rachel Martini 4,  Brian Stonaker 4,  Richard Boateng 5,  Joseph K Oppong 5,  Ernest K Adjei 5,  Baffour Awuah 5,  Ishmael Kyei 6,  Frances S Aitpillah 5,  Michael O Adinku 6,  Kwasi Ankomah 5,  Ernest B Osei-Bonsu 5,  Kofi K Gyan 4,  Nasser K Altorki 7,  Esther Cheng 8,  Paula S Ginter 9,  Syed Hoda 8,  Lisa Newman 4,  Olivier Elemento 1,  Melissa B Davis 1 10,  M Laura Martin 1,  Jill Bargonetti 2 11 12
Affiliations

Affiliations

  • 1 Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, New York, NY10021.
  • 2 The Department of Biological Sciences Hunter College, Belfer Building, City University of New York, New York, NY10021.
  • 3 Center for Clinical Cancer Genetics and Global Health and Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637.
  • 4 Department of Surgery, Weill Cornell Medicine, New York, NY10021.
  • 5 Komfo Anokye Teaching Hospital, Kumasi, Ghana.
  • 6 Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
  • 7 Department of Cardiothoracic Surgery, Weill Cornell Medical College, New York, NY.
  • 8 Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY.
  • 9 Department of Pathology, NYU Langone Hospital-Long Island, Mineola, NY.
  • 10 Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, 720 Westview Drive, Atlanta, GA 30310.
  • 11 Department of Cell and Developmental Biology, Weill Cornell Medical College, New York City, NY 10021.
  • 12 The Graduate Center Biology and Biochemistry Programs of City University of New York, New York, NY 10016.
PMID: 38076873 DOI: 10.1101/2023.06.22.544406
Abstract

Poly (ADP-ribose) polymerase inhibitors (PARPi) are used for patients with BRCA1/2 mutations, but patients with Other mutations may benefit from PARPi treatment. Another mutation that is present in more cancers than BRCA1/2 is mutation to the TP53 gene. In 2D breast Cancer cell lines, mutant p53 (mtp53) proteins tightly associate with replicating DNA and Poly (ADP-ribose) polymerase (PARP) protein. Combination drug treatment with the alkylating agent temozolomide and the PARPi talazoparib kills mtp53 expressing 2D grown breast Cancer cell lines. We evaluated the sensitivity to the combination of temozolomide plus PARPi talazoparib treatment to breast and lung Cancer patient-derived tumor organoids (PDTOs). The combination of the two drugs was synergistic for a cytotoxic response in PDTOs with mtp53 but not for PDTOs with wtp53. The combination of talazoparib and temozolomide induced more DNA double-strand breaks in mtp53 expressing organoids than in wild-type p53 expressing organoids as shown by increased γ-H2AX protein expression. Moreover, breast Cancer tissue microarrays (TMAs) showed a positive correlation between stable p53 and high PARP1 expression in sub-groups of breast cancers, which may indicate sub-classes of breast cancers sensitive to PARPi therapy. These results suggest that mtp53 could be a biomarker to predict response to the combination of PARPi talazoparib-temozolomide treatment.

Keywords

DNA double-strand breaks; PARP inhibitor; Patient-derived tumor organoids; mutant p53; synergistic cytotoxicity.

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