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.
- 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].
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.