Title:MYC-mediated Synthetic Lethality for Treatment of Hematological Malignancies
Volume: 15
Issue: 1
Author(s): Xin Li, Xin A. Zhang, Wei Xie, Xiaoqing Li and Shiang Huang
Affiliation:
Keywords:
c-MYC, hematological malignancy, oncogene addiction, small molecule inhibitor, synthetic lethality, targeted
therapy, tumorigenesis.
Abstract: Deregulated c-MYC expression is found in many human malignancies. MYC activation induces
multiple lineages of hematological malignancies in single Myc transgenic mice. MYC inactivation causes
tumor regression. MYC is therefore an attractive target for cancer treatment. However, little progress has
been made in the development and application of targeted MYC inactivation in clinical practice. In double
Myc transgenic mouse models, Myc-driven leukemogenesis and lymphomagenesis can be accelerated by transduction of
non-MYC oncogenes, leading to dual addiction to MYC and the non-MYC oncogenes. Wang et al. (2004) first
established the concept of MYC-mediated synthetic lethality (MYC-SL). MYC overexpression sensitized cells to TRAILand
DR5-agonist-induced apoptosis. This suggests that MYC-dependent tumor cells may be killed by targeting partner
oncogenes of MYC. Many small molecule inhibitors (SMIs) have been proven to induce MYC-SL by targeting AUK-B,
Brd4, CDK1, CHK1, MCL-1, the mTOR/4E-BP1/eIF4E pathway, and PIM1/2. Compared with conventional treatment
approaches, SMI-induced MYC-SL displays highly selective anticancer activity and much lower cytotoxicity to normal
cells. SMI-induced MYC-SL can reverse eIF4F- and PIM2-induced multiple chemoresistance. The combination of an
SMI with chemotherapeutic agents can elevate chemotherapy efficacy by enhancing chemosensitivity. This combination
will be a promising novel approach to treating MYC-dependent tumors by inducing MYC-SL.
