Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy?

Abstract

Unrestrained proliferation is a common feature of malignant neoplasms. Targeting the cell cycle is a therapeutic strategy to prevent unlimited cell division. Recently developed rationales for these selective inhibitors can be subdivided into two categories with antithetical functionality. One applies a "brake" to the cell cycle to halt cell proliferation, such as with inhibitors of cell cycle kinases. The other "accelerates" the cell cycle to initiate replication/mitotic catastrophe, such as with inhibitors of cell cycle checkpoint kinases. The fate of cell cycle progression or arrest is tightly regulated by the presence of tolerable or excessive DNA damage, respectively. This suggests that there is compatibility between inhibitors of DNA repair kinases, such as PARP inhibitors, and inhibitors of cell cycle checkpoint kinases. In the present review, we explore alterations to the cell cycle that are concomitant with altered DNA damage repair machinery in unfavorable neuroblastomas, with respect to their unique genomic and molecular features. We highlight the vulnerabilities of these alterations that are attributable to the features of each. Based on the assessment, we offer possible therapeutic approaches for personalized medicine, which are seemingly antithetical, but both are promising strategies for targeting the altered cell cycle in unfavorable neuroblastomas.

Keywords: 11q loss; DNA damage response; MYCN; RAS; cell cycle; checkpoint; inhibitor; neuroblastoma; replication stress; telomere.

Figure 1

Schematic representation of responsible molecules for applying “brakes” on the neuroblastoma cell cycle. Current druggable targets were depicted.

Figure 2

Schematic representation of responsible molecules for the “acceleration” of the neuroblastoma cell cycle. Current druggable targets are depicted. Possible catastrophic cell deaths caused by oncogenic stresses are shown.

Figure 3

Schematic representation of candidate targeted drugs for two types of unfavorable neuroblastomas. (A) MYCN-amplified neuroblastoma, (B) non-MYCN amplified neuroblastoma with 11q loss. Red T-bars indicate putting the “brakes” on the cell cycle. Blue arrows indicate “acceleration” of the cell cycle.