Many human cancers depend on deregulated and overexpressed MYC for their sustained growth and proliferation, yet pharmacological inhibition of this oncogenic transcription factor has proved daunting. Recent insights into how MYC promotes the cancer cell state suggests an avenue through which its oncogenic properties could be exploited therapeutically. When overexpressed, MYC acts as a global amplifier of transcription, leading to massively upregulated expression of all actively transcribed genes. Moreover, oncogenic MYC is transcriptionally regulated by large enhancer regions, or super-enhancers (SEs), that facilitate its high-level expression and are acutely sensitive to perturbation. Given the emerging status of oncogenic MYC as a SE-associated transcriptional amplifier, we sought to selectively target the mechanisms governing its transcriptional regulation. The transcription cycle of RNA polymerase II is governed by a group of cyclin-dependent kinases (CDKs), including CDKs 7-13, with critical roles in transcription initiation and elongation. We hypothesize that inhibition of CDK7, a CDK with primary roles in transcription regulation, selectively targets MYC-overexpressing cancer cells by interfering with enhancer-promoter control of gene transcription and thus MYC-driven global transcriptional amplification. In preliminary studies, we demonstrated striking activity and selectivity by THZ1, a novel prototype covalent CDK7 inhibitor, in MYCN-amplified neuroblastoma (NB) cells compared to those without MYCN amplification. This effect was associated with inhibition of global MYCN-dependent transcriptional amplification and preferentially reduced expression of SE-associated genes, especially MYCN, without toxicity to normal tissues. To validate CDK7 inhibition as a tractable therapeutic strategy against MYCN-amplified NB, we now address three pivotal research questions.
Aim 1 : Will newer THZ1 analogs with improved pharmacokinetics, in combination with targeted or standard cytotoxic agents, induce durable responses in MYCN-amplified NB? Aim 2: What is the basis for the selective lethality of CDK7 inhibition in MYCN-amplified NB cells? Aim 3: What are the mechanisms of resistance to THZ1? The results we generate are expected to yield important insights into approaches that could be used to inhibit amplified MYCN function in high-risk NB, and therefore may provide a compelling rationale for the treatment of other cancers with deregulated expression of MYC family proteins, which represents the long-term goal of our research.

Public Health Relevance

The potent oncogene MYCN is amplified in half of high-risk neuroblastoma cases, but devising strategies to inhibit this transcription factor has been challenging. We propose to take advantage of recent findings that oncogenic MYC upregulates the active transcriptional program in cancer cells and is transcriptionally regulated by large enhancer regions that facilitate its high-level expression and that are especially sensitive to perturbation. By using a novel covalent inhibitor of CDK7, a kinase that has crucial roles in gene transcription and cell cycle regulation, we will explore the potential of targeting MYCN-induced transcription as a novel therapeutic strategy for patients with MYCN-amplified neuroblastoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA197336-02
Application #
9238746
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Alley, Michael C
Project Start
2016-03-07
Project End
2021-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
2
Fiscal Year
2017
Total Cost
$366,972
Indirect Cost
$121,981
Name
Dana-Farber Cancer Institute
Department
Type
Independent Hospitals
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Zeng, Mei; Kwiatkowski, Nicholas P; Zhang, Tinghu et al. (2018) Targeting MYC dependency in ovarian cancer through inhibition of CDK7 and CDK12/13. Elife 7:
Gao, Yang; Zhang, Tinghu; Terai, Hideki et al. (2018) Overcoming Resistance to the THZ Series of Covalent Transcriptional CDK Inhibitors. Cell Chem Biol 25:135-142.e5
Sengupta, Satyaki; George, Rani E (2017) Super-Enhancer-Driven Transcriptional Dependencies in Cancer. Trends Cancer 3:269-281