Details

Autor(en) / Beteiligte

• Mani, Chinnadurai
• Tripathi, Kaushlendra
• Omy, Tasmin R.
• Reedy, Mark
• Manne, Upender
• Palle, Komaraiah

Titel

GLI1-targeting drugs induce replication stress and homologous recombination deficiency and synergize with PARP-targeted therapies in triple negative breast cancer cells

Ist Teil von

• Biochimica et biophysica acta. Molecular basis of disease, 2022-02, Vol.1868 (2), p.166300-166300, Article 166300

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• Triple negative breast cancer (TNBC), an aggressive and highly metastatic subtype of breast cancer. Glioma-associated oncogene 1 (GLI1) is a transcription factor and effector of the Hedgehog (Hh) signaling pathway, and is predictive of poor survival for TNBC patients. A nanostring DNA Damage Response (DDR) mRNA panel was used to identify GLI1-induced regulation of DDR genes. Western blots, immunohistochemistry and immunofluorescence were used to evaluate protein expression. Colony assays and mammosphere formation assays were utilized to assess survival of cancer cells. Flow cytometry analyses were employed to evaluate changes in the cell cycle profile, and DNA fiber assays were used to analyze alterations in replication dynamics in TNBC cells. The UALCAN portal and Ensemble programs were used for computational analysis of TCGA data. CompuSyn software was used to calculate combination index (CI) values to assess synergism in drug combination experiments. Inhibition of GLI1 in TNBC cells transcriptionally downregulate expression of FANCD2 and its foci formation, and causes a homologous recombination repair (HR) deficiency. As HR-deficient cancer cells are sensitive to PARP-targeted therapies, we evaluated a combination of the GLI1 inhibitor, GANT61, and a PARP inhibitor (olaparib) in TNBC cells. Combination of GANT61 and olaparib elevated DNA damage levels and these drug combinations caused synergistic lethality to TNBC cells. Aberrantly activated GLI1 regulates HR-mediated DNA repair by transcriptionally regulating FANCD2 to overcome chemotherapy-induced replication stress and DNA damage, and it contributes to resistance of TNBC cells to therapeutics. •GLI1 transcriptionally regulates FANCD2 in breast cancer cells.•Inhibition of FANCD2 by GLI1 induces homologous recombination deficiency (HRD).•HRD cells can be sensitized using PARP inhibitors like olaparib.•Combination of GLI1 and PARP inhibitors induces synergistic lethality in breast cancer cells.