Integrated pan-cancer gene expression and drug sensitivity analysis reveals SLFN11 mRNA as a solid tumor biomarker predictive of sensitivity to DNA-damaging chemotherapy

Abstract

Background: Precision oncology seeks to integrate multiple layers of data from a patient's cancer to effectively tailor therapy. Conventional chemotherapies are sometimes effective but accompanied by adverse events, warranting the identification of a biomarker of chemosensitivity.

Objective: Identify an mRNA biomarker that predicts chemosensitivity across solid tumor subtypes.

Methods: We performed a pan-solid tumor analysis integrating gene expression and drug sensitivity profiles from 3 cancer cell line datasets to identify transcripts correlated with sensitivity to a panel of chemotherapeutics. We then tested the ability of an mRNA biomarker to predictive clinical outcomes in cohorts of patients with breast, lung, or ovarian cancer.

Results: Expression levels of several mRNA transcripts were significantly correlated with sensitivity or resistance chemotherapeutics in cancer cell line datasets. The only mRNA transcript significantly correlated with sensitization to multiple classes of DNA-damaging chemotherapeutics in all 3 cell line datasets was encoded by Schlafen Family Member 11 (SLFN11). Analyses of multiple breast, lung, and ovarian cancer patient cohorts treated with chemotherapy confirmed SLFN11 mRNA expression as a predictive biomarker of longer overall survival and improved tumor response.

Conclusions: Tumor SLFN11 mRNA expression is a biomarker of sensitivity to an array of DNA-damaging chemotherapeutics across solid tumor subtypes.

Fig 1. SLFN11 mRNA levels are strongly correlated with sensitivity to chemotherapeutics in cancer cells.

A) mRNA levels for each gene were compared with drug sensitivity to a panel of chemotherapeutics across the CTRP (IC₅₀), GDSC (AUC), and NCI60 (IC₅₀) datasets. Pearson correlation values were plotted for each gene for SN38, mitomycin, and gemcitabine as representative chemotherapeutics. B) SLFN11 mRNA levels were compared with drug sensitivity as in (A) by Pearson correlation. Each point represents the IC₅₀ of a given drug. Horizontal lines indicate mean ± SEM for each drug class. Black filled, white-filled, and color-filled symbols indicate p≤0.001, p≤0.05, and p>0.05, respectively.

Fig 2. SLFN11 mRNA expression is commonly associated with chemosensitivity in cancer cell lines.

Numbers of genes with expression correlated with sensitivity (R≤-0.2) or resistance (R≥0.2) to >50% of drugs within a class in ≥2 databases (CTRP, GDSC, or NCI60) are indicated. Genes are listed in Table 2.

Fig 3. SLFN11 expression is associated with improved survival outcomes in breast, lung, and ovarian cancer patients treated with chemotherapy.

RNA expression and survival data were obtained for primary breast, lung, and ovarian tumors from 4 datasets containing information from 61 breast cancer patients (A/D), 55 and196 lung cancer patients (B/E and C/F, respectively), and 110 ovarian cancer patients (G). Patients were dichotomized into High vs. Low tumor SLFN11 mRNA based on expression above or below the median. Survival analyses were performed for all patients in aggregate in (A-C), and only for patients who received chemotherapy (D-G). Groups were compared by log-rank test.

Fig 4. Patients with tumors highly responsive to chemotherapy have high SLFN11 transcript levels.

Z-score normalized RNA expression and tumor response data were obtained for primary breast and ovarian tumors from 2 datasets containing information from 115 breast cancer patients (A) and 75 ovarian cancer patients (B) treated with neoadjuvant chemotherapy. Breast cancer patients were divided into patients who had a pathologic Complete Response after chemotherapy (pCR), to those that did not (non-pCR), and SLFN11 expression was compared by Student t-test with Welch’s correction. Ovarian cancer patients were divided into patients who were highly sensitive (HS; defined as DFS>732 days according to [15]) or not (non-HS), and analyzed as above.