# CK2–HTATSF1–TOPBP1 signaling axis modulates tumor chemotherapy response

## TL;DR

A signaling pathway involving CK2, HTATSF1, and TOPBP1 affects how tumors respond to chemotherapy, with its hyperactivation making breast tumors less responsive.

## Contribution

The study reveals the clinical role of the CK2–HTATSF1–TOPBP1 axis in tumor chemotherapy response and HR deficiency.

## Key findings

- The CK2–HTATSF1–TOPBP1 axis is hyperactivated in multiple cancers and reduces chemotherapy response in breast tumors.
- Loss-of-function mutations in this pathway correlate with higher HR deficiency scores and increased sensitivity to PARP inhibitors or platinum drugs.
- The pathway's integrity is linked to tumorigenesis and serves as an indicator of HR status in tumors.

## Abstract

Homologous recombination (HR) plays a key role in maintaining genomic stability, and the efficiency of the HR system is closely associated with tumor response to chemotherapy. Our previous work reported that CK2 kinase phosphorylates HIV Tat-specific factor 1 (HTATSF1) Ser748 to facilitate HTATSF1 interaction with TOPBP1, which in turn, promotes RAD51 recruitment and HR repair. However, the clinical implication of the CK2–HTATSF1–TOPBP1 pathway in tumorigenesis and chemotherapeutic response remains to be elucidated. Here, we report that the CK2–HTATSF1–TOPBP1 axis is generally hyperactivated in multiple malignancies and renders breast tumors less responsive to chemotherapy. In contrast, deletion mutations of each gene in this axis, which also occur in breast and lung tumor samples, predict higher HR deficiency scores, and tumor cells bearing a loss-of-function mutation of HTATSF1 are vulnerable to poly(ADP-ribose) polymerase inhibitors or platinum drugs. Taken together, our study suggests that the integrity of the CK2–HTATSF1–TOPBP1 axis is closely linked to tumorigenesis and serves as an indicator of tumor HR status and modulates chemotherapy response.