Genomic scarring score predicts the response to PARP inhibitors in non-small cell lung cancer

Abstract

PARP inhibitors (PARPi) have shown efficacy in tumours harbouring mutations in homologous recombination repair (HRR) genes. Somatic HRR mutations have been described in patients with Non-Small Cell Lung Cancer (NSCLC), but PARP inhibitors (PARPi) are not yet a therapeutic option. Here we assessed the homologous recombination status of early-stage NSCLC and explored the therapeutic benefit of PARPi in preclinical models. The Genomic Scarring Score GSS (GSS) and HRR mutation profile of 136 patients were assessed. High GSS (h-GSS) was observed in 39 (28.7%) patients half of which carried pathogenic/likely pathogenic somatic HRR mutations. TP53 mutations were significantly enriched in h-GSS tumours (p < 0.001). Olaparib significantly delayed tumour growth in h-GSS but not l-GSS Patient-derived Xenografts (PDXs), while patients with h-GSS/TP53mut tumours respond favourably to adjuvant platinum-based chemotherapy. Our functional data clearly support the idea that the use of GSS rather than the mutational status of HRR genes could select patients for administration of PARPi.

Fig. 1. GSS and HR gene mutations in an early NSCLC patient cohort.

A Number of l-GSS and h-GSS tumours in the patient cohort. B Break-down of the different subgroups of l-GSS and h-GSS tumours across the GSS scale. C Heat map of HRR-related P/LP and VUS mutations. Germline mutations are shown in yellow font. In cases with P/LP mutations, VUS are not shown.

Fig. 2. HR gene expression and RAD51 status in the NSCLC cohort.

A mRNA expression of HR genes in l-GSS (left) vs h-GSS (right) tumours, expression is normalized against β-actin, ***: p < 0.001, n = at least 8 samples/group. B RAD51 foci formation in l-GSS vs h-GSS primary tumours, pictures are representative from n = 8 patients/group.

Fig. 3. Correlation of TP53 status with GSS.

A Prevalence of P/LP TP53 mutations across the GSS scale. B Heat map of TP53 P/LP and VUS mutations. C Correlation of GSS score and TP53 mutation VAF. D Correlation of GSS score and HRR VAF. E Correlation of TP53 and HRR VAF. For samples with more than one HRR mutation, the sum of VAFs of the separate mutations is plotted. In cases with P/LP mutations, VUS are not shown.

Fig. 4. Frequency of RAD51 foci upon CDDP treatment.

A Comparison of RAD51 foci formation in primary tumours and PDX, representative of 6 different comparisons, scale bar 10 μm. B Response of h-GSS and l-GSS PDXs to in vivo DNA damage induction (6 mg/kg CDDP for 24 h), scale bars 20 μm. C Quantification of (B), percentage of nuclei with >10 RAD51 foci in l-GSS (n = 7) vs h-GSS (n = 4) PDX, *: p < 0.05, 3 different fields per sample were quantified.

Fig. 5. Response of l-GSS vs h-GSS PDX to olaparib administration.

Statistical significance was determined with 2-way ANOVA and significance per time point was determined via multiple comparisons analysis, *: p < 0.05, **: p < 0.01, ***: p < 0.001, ****: p < 0.0001. Patient number, GSS and cohort sizes are indicated for each experiment.

Fig. 6. Predictive value of GSS and TP53 status in platinum response.

A DFI of patients treated with platinum-based chemotherapy in the adjuvant setting. B OS of patients treated with platinum-based chemotherapy at any line.