Synergistic targeting of CHK1 and mTOR in MYC-driven tumors

Carcinogenesis. 2021 Apr 17;42(3):448-460. doi: 10.1093/carcin/bgaa119.

Abstract

Deregulation of v-myc avian myelocytomatosis viral oncogene homolog (MYC) occurs in a broad range of human cancers and often predicts poor prognosis and resistance to therapy. However, directly targeting oncogenic MYC remains unsuccessful, and indirectly inhibiting MYC emerges as a promising approach. Checkpoint kinase 1 (CHK1) is a protein kinase that coordinates the G2/M cell cycle checkpoint and protects cancer cells from excessive replicative stress. Using c-MYC-mediated T-cell acute lymphoblastic leukemia (T-acute lymphoblastic leukemia) and N-MYC-driven neuroblastoma as model systems, we reveal that both c-MYC and N-MYC directly bind to the CHK1 locus and activate its transcription. CHIR-124, a selective CHK1 inhibitor, impairs cell viability and induces remarkable synergistic lethality with mTOR inhibitor rapamycin in MYC-overexpressing cells. Mechanistically, rapamycin inactivates carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD), the essential enzyme for the first three steps of de novo pyrimidine synthesis, and deteriorates CHIR-124-induced replicative stress. We further demonstrate that dual treatments impede T-acute lymphoblastic leukemia and neuroblastoma progression in vivo. These results suggest simultaneous targeting of CHK1 and mTOR as a novel and powerful co-treatment modality for MYC-mediated tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Cell Line, Tumor
  • Checkpoint Kinase 1 / antagonists & inhibitors*
  • Checkpoint Kinase 1 / genetics
  • Checkpoint Kinase 1 / metabolism
  • Datasets as Topic
  • Disease Progression
  • Drug Synergism
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Mice
  • N-Myc Proto-Oncogene Protein / metabolism
  • Neuroblastoma / drug therapy*
  • Neuroblastoma / genetics
  • Neuroblastoma / mortality
  • Neuroblastoma / pathology
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Prognosis
  • Proto-Oncogene Proteins c-myc / metabolism
  • Quinolines / pharmacology
  • Quinolines / therapeutic use
  • Quinuclidines / pharmacology
  • Quinuclidines / therapeutic use
  • Sirolimus / pharmacology
  • Sirolimus / therapeutic use
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • CHIR-124
  • MYC protein, human
  • MYCN protein, human
  • N-Myc Proto-Oncogene Protein
  • Proto-Oncogene Proteins c-myc
  • Quinolines
  • Quinuclidines
  • MTOR protein, human
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • TOR Serine-Threonine Kinases
  • Sirolimus