Synergistic targeting of CHK1 and mTOR in MYC-driven tumors

by Selleckchem | Oct 11 2023

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.

Comments:

The passage you provided discusses the deregulation of the MYC oncogene in various human cancers and the challenges in directly targeting MYC. Instead, the focus is on indirectly inhibiting MYC through the inhibition of checkpoint kinase 1 (CHK1), a protein kinase that protects cancer cells from replicative stress. The study uses T-cell acute lymphoblastic leukemia (T-ALL) and neuroblastoma as model systems and demonstrates that both c-MYC and N-MYC directly bind to the CHK1 gene and activate its transcription.

The authors investigated the effects of CHIR-124, a selective CHK1 inhibitor, on cell viability in MYC-overexpressing cells. They found that CHIR-124 impairs cell viability and shows synergistic lethality when combined with the mTOR inhibitor rapamycin. Rapamycin inhibits carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD), which are essential enzymes for the early steps of de novo pyrimidine synthesis. This disruption of pyrimidine synthesis contributes to replicative stress induced by CHIR-124.

Furthermore, the study conducted in vivo experiments and observed that the dual treatment targeting CHK1 and mTOR impedes the progression of T-ALL and neuroblastoma.

In summary, the study suggests that simultaneously targeting CHK1 and mTOR could serve as a novel and potent co-treatment strategy for MYC-mediated tumors, such as T-ALL and neuroblastoma. By inhibiting CHK1 and disrupting pyrimidine synthesis, along with mTOR inhibition, the treatment induces replicative stress and impairs cell viability, potentially providing a therapeutic approach for cancers with MYC deregulation.