DNA Damage Repair Proteins, HSP27, and Phosphorylated-HSP90α as Predictive/Prognostic Biomarkers of Platinum-based Cancer Chemotherapy: An Exploratory Study

Abstract

Platinum analogs are commonly used for cancer treatment. There is increasing interest in finding biomarkers which could predict and overcome resistance, because to date there is no reliable predictive/prognostic marker for these compounds. Here we studied the immunohistochemical expression of proteins involved in DNA damage response and repair (γH2AX, 53BP1, ERCC1, MLH1, and MSH2) in primary tumor tissues from patients treated with platinum-based chemotherapy. Levels and localization of Heat Shock Protein (HSP)27 and phospho-(Thr5/7)-HSP90α (p-HSP90α) were also determined. The implications in clinical response, disease-free survival and overall survival were analyzed. High γH2AX and 53BP1 expressions were associated with poor clinical response. Nuclear p-HSP90α, as well as nuclear absence and low cytoplasmic expression of HSP27 correlated with good response. Patients with high γH2AX and high cytoplasmic HSP27 expressions had shorter overall survival and disease-free survival. MLH1, MSH2, or ERCC1 were not associated with clinical response or survival. We report the potential utility of p-HSP90α, HSP27, γH2AX, and 53BP1 as predictive/prognostic markers for platinum-based chemotherapy. We present the first study that evaluates the predictive and prognostic value of p-HSP90α in primary tumors. Our research opens new possibilities for clinical oncology and shows the usefulness of immunohistochemistry for predicting chemotherapy response and prognosis in cancer.

Relevance of Comet Assay and Phosphorylated-Hsp90α in Cancer Patients’ Peripheral Blood Leukocytes as Tools to Assess Cisplatin-based Chemotherapy Clinical Response and Disease Outcome

“…Recently, we reported that nuclear p-Hsp90α in tumor tissues correlated with good clinical response in patients treated with platinum-based chemotherapy. 17 However, the clinical implications of p-Hsp90α in PBL from cancer patients remain still unknown. For the first time, we evaluated by immunocytochemistry the nuclear and cytoplasmic expression of p-Hsp90α in pre-chemotherapy PBL from cancer patients at basal conditions and after cPt exposure.…”

“…Tumor tissues known to express γH2AX, 53BP1, and p-Hsp90α Thr 5/7 were included as positive controls as described previously. 17…”

“…Response to chemotherapy was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) which are defined as complete response (CR; the disappearance of all target lesions), partial response (PR; at least a 30% decrease in the sum of diameters of the lesions), progressive disease (PD; at least a 20% increase in the sum of diameters of the lesions), or stable disease (SD; neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD). 17,22 Follow-Up…”

“…On the other hand, p-Hsp90α evaluation can provide information for patient management and treatment. 11,17 The associations of the studied markers with clinical res-ponse, disease-free survival (DFS), and overall survival (OS) were also determined.…”

Microsatellite instability states serve as predictive biomarkers for tumors chemotherapy sensitivity

“…There are also many studies on the development of markers to predict chemotherapy response based on these mechanisms, and these markers include the homologous recombination deficiency (HRD) score, 19 heat shock protein 90α (HSP90α), 20 and Kirsten rat sarcoma virus (KRAS) gene. 21 However, the most widely used biomarker in clinical practice is MSI status.…”