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. 2022 Jan 27;14(3):641.
doi: 10.3390/cancers14030641.

Modulation of DNA Damage Response by SAM and HD Domain Containing Deoxynucleoside Triphosphate Triphosphohydrolase (SAMHD1) Determines Prognosis and Treatment Efficacy in Different Solid Tumor Types

Eudald Felip  1   2   3 , Lucía Gutiérrez-Chamorro  1 , Maica Gómez  4 , Edurne Garcia-Vidal  1 , Margarita Romeo  2   3 , Teresa Morán  2   3 , Laura Layos  2   3 , Laia Pérez-Roca  5 , Eva Riveira-Muñoz  1 , Bonaventura Clotet  1 , Pedro Luis Fernandez  4 , Ricard Mesía  2   3 , Anna Martínez-Cardús  2   3 , Ester Ballana  1 , Mireia Margelí  2   3
Affiliations

Modulation of DNA Damage Response by SAM and HD Domain Containing Deoxynucleoside Triphosphate Triphosphohydrolase (SAMHD1) Determines Prognosis and Treatment Efficacy in Different Solid Tumor Types

Eudald Felip et al. Cancers (Basel). .

Abstract

SAMHD1 is a deoxynucleotide triphosphate (dNTP) triphosphohydrolase with important roles in the control of cell proliferation and apoptosis, either through the regulation of intracellular dNTPs levels or the modulation of the DNA damage response. However, SAMHD1's role in cancer evolution is still unknown. We performed the first in-depth study of SAMHD1's role in advanced solid tumors, by analyzing samples of 128 patients treated with chemotherapy agents based on platinum derivatives and/or antimetabolites, developing novel in vitro knock-out models to explore the mechanisms driving SAMHD1 function in cancer. Low (or no) expression of SAMHD1 was associated with a positive prognosis in breast, ovarian, and non-small cell lung cancer (NSCLC) cancer patients. A predictive value was associated with low-SAMHD1 expression in NSCLC and ovarian patients treated with antimetabolites in combination with platinum derivatives. In vitro, SAMHD1 knock-out cells showed increased γ-H2AX and apoptosis, suggesting that SAMHD1 depletion induces DNA damage leading to cell death. In vitro treatment with platinum-derived drugs significantly enhanced γ-H2AX and apoptotic markers expression in knock-out cells, indicating a synergic effect of SAMHD1 depletion and platinum-based treatment. SAMHD1 expression represents a new strong prognostic and predictive biomarker in solid tumors and, thus, modulation of the SAMHD1 function may constitute a promising target for the improvement of cancer therapy.

Keywords: NSCLC; SAMHD1; breast cancer; ovarian cancer; solid tumors.

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Conflict of interest statement

M.R. declares a consulting and advisory role for GSK, AstraZeneca, and MSD; and research funding from Pfizer, Clovis, GSK, AstraZeneca, and MSD. T.M. declares a consulting and advisory role for AstraZeneca, BMS, and MSD. L.L. declares a consulting or advisory role for Celgene and Sanofi and travel expenses from Sanofi, Merck, Roche, Amgen, and Ipsen. Ricard Mesia declares a consulting and advisory role for Merck, MSD, Roche, AstraZeneca, BEM, the speaker’s bureau for Merck, MSD, BMS, and Roche. M.M. declares a consulting and advisory role for Novartis, Pfizer, Pier Fabre, and Roche; research funding from Roche, Eisai, AstraZeneca, and travel expenses from Roche. The rest authors declare no potential conflict of interest.

Figures

Figure 1
Figure 1
Expression of SAMHD1 protein by immunochemistry in tumor samples. (A–E) Representative microscopy images of SAMHD1 expression in paraffin-embedded tumor biopsies for the different tumor types included in the study, from ovarian (A), NSCLC (B), breast (C), pancreas (D), and rectal (E). Images on the left represent negative SAMHD1 expressing tumors and on the right positive expressing tumors in all cases except in rectum (E), where all analyzed tumors presented extremely high levels of SAMHD1 expression. High expression of SAMHD1 observed in lymphocytic cells infiltrating in the tumors was used as a positive control of immunohistochemistry for negative or low expressing biopsies. In case of negative or low expressing biopsies, high expression of SAMHD1 was observed in lymphocytic cells. (F) Summary of all analyzed biopsies stratified based on SAMHD1 expression in positive or negative (cutoff >25% of tumor cells). N, neoplastic cells; L, lymphocytes, H, healthy tissue. In higher magnification images, red arrows indicate neoplastic cells and red asterisks lymphocytic cells. SAMHD1 expression was exclusively nuclear.
Figure 2
Figure 2
Prognostic value of SAMHD1 in ovarian, lung and breast cancer cohorts. Kaplan–Meier curves of disease-free survival (DFS) (A) and OS since cancer diagnostic (B) according to SAMHD1 status for different tumor types. From left to right: ovarian, NSCLC and breast. Kaplan–Meier curves are represented. SAMHD1 expression below 25% in cancer cells was considered as negative SAMHD1 (red lines) and equal or above 25% was considered as positive SAMHD1 tumors (black lines). Median survival times with CI 95% of both groups are showed. Log rank test was used to test the significance and censored patients are indicated by vertical line.
Figure 3
Figure 3
Predictive value of SAMHD1 in ovarian, lung and breast cancer cohorts treated with antimetabolite-containing regimens. Kaplan–Meier curves of time to progression (TTP) (A) and overall survival since cohort treatment initiation (OS) (B) for each tumor according to SAMHD1 status for different tumor types. From left to right: ovarian, NSCLC and breast. SAMHD1 expression below 25% in cancer cells was considered as negative SAMHD1 (red lines) and equal or above 25% was considered as positive SAMHD1 tumors (black lines). Median survival times with CI 95% of both groups are showed. Log rank test was used to test the significance and censored patients are indicated by vertical line.
Figure 4
Figure 4
SAMHD1-depletion induces DNA damage and apoptosis after treatment with platinum derivatives. (A) The DNA damage marker γH2AX expression in WT and SAMHD1-KO cell lines. Representative flow cytometry histogram (left) with overlay of WT (grey) and SAMHD1-KO (blue) T47D cells comparing γH2AX expression. Histogram has been normalized to the modal values. Bar graph (right) showing mean fluorescence intensity (MFI) of γH2AX in WT and SAMHD1-KO T47D cells. Mean ± SEM of four independent experiments is shown. (B) Cell apoptosis measured as PARP cleaved and cleaved caspase 3 in WT and SAMHD1-KO cell lines. Representative western blot (left) and quantification (right) showing differential expression of PARP cleaved and cleaved caspase 3 in T47D WT and SAMHD1-KO cells. Mean ± SEM of four independent experiments is shown. (C) Left panel, representative flow cytometry histograms measuring γH2AX expression in WT (grey) and SAMHD1-KO (blue) T47D cells treated with carboplatin, cisplatin, and fluorouracil for 24 h. Right panel, bar graphs representing MFI of γH2AX expression in WT and KO T47D cells after treatment with different concentrations of carboplatin, cisplatin, and fluorouracil. Mean ± SEM of four different experiments is shown. (D) Representative western blots (upper panel) and quantification (bottom panel) showing PARP cleaved and cleaved caspase 3 expression in WT and SAMHD1-KO T47D cells treated with carboplatin, cisplatin and fluorouracil for 24 h. Mean ± SEM of four different experiments is shown. *, p < 0.05; **, p < 0.01.
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