2. Academic Validation
  3. Molecular correlates of sensitivity to PARP inhibition beyond homologous recombination deficiency in pre-clinical models of colorectal cancer point to wild-type TP53 activity

Molecular correlates of sensitivity to PARP inhibition beyond homologous recombination deficiency in pre-clinical models of colorectal cancer point to wild-type TP53 activity

  • EBioMedicine. 2020 Sep;59:102923. doi: 10.1016/j.ebiom.2020.102923.
Jørgen Smeby 1,  Kushtrim Kryeziu 2,  Kaja C G Berg 3,  Ina A Eilertsen 3,  Peter W Eide 2,  Bjarne Johannessen 3,  Marianne G Guren 4,  Arild Nesbakken 5,  Jarle Bruun 2,  Ragnhild A Lothe 3,  Anita Sveen 6
Affiliations

Affiliations

  • 1 Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway;; K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway; Department of Oncology, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
  • 2 Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway;; K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway.
  • 3 Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway;; K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
  • 4 K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway; Department of Oncology, Oslo University Hospital, Oslo, Norway.
  • 5 K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, Norway.
  • 6 Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway;; K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. Electronic address: [email protected].
PMID: 32799124 DOI: 10.1016/j.ebiom.2020.102923
Abstract

Background: PARP inhibitors are active in various tumour types beyond BRCA-mutant cancers, but their activity and molecular correlates in colorectal Cancer (CRC) are not well studied.

Methods: Mutations and genome-wide mutational patterns associated with homologous recombination deficiency (HRD) were investigated in 255 primary CRCs with whole-exome sequencing and/or DNA copy number data. Efficacy of five PARP inhibitors and their molecular correlates were evaluated in 93 CRC cell lines partly annotated with mutational-, DNA copy number-, and/or gene expression profiles. Post-treatment gene expression profiling and specific protein expression analyses were performed in two pairs of PARP Inhibitor sensitive and resistant cell lines.

Findings: A subset of microsatellite stable (MSS) CRCs had truncating mutations in homologous recombination-related genes, but these were not associated with genomic signatures of HRD. Eight CRC cell lines (9%) were sensitive to PARP inhibition, but sensitivity was not predicted by HRD-related genomic and transcriptomic signatures. In contrast, drug sensitivity in MSS cell lines was strongly associated with TP53 wild-type status (odds ratio 15.7, p = 0.023) and TP53-related expression signatures. Increased downstream TP53 activity was among the primary response mechanisms, and TP53 inhibition antagonized the effect of PARP inhibitors. Wild-type TP53-mediated suppression of RAD51 was identified as a possible mechanism of action for sensitivity to PARP inhibition.

Interpretation: PARP inhibitors are active in a subset of CRC cell lines and preserved TP53 function may increase the likelihood of response.

Keywords

Colorectal cancer; PARP inhibition; RAD51; TP53; gene expression; homologous recombination deficiency; mutational signatures.

Figures
Products