Dr Luo on the Potential Use of KB-0742 In MYC-Amplified Tumors

Jia Luo, MD, medical oncologist, Lowe Center for Thoracic Oncology, cancer researcher, Dana-Farber Cancer Institute, instructor in medicine, Harvard Medical School, discusses the potential use of KB-0742 to target specific MYC-driven tumor types, as well as challenges in the detection of MYC amplification or overexpression in clinical practice.

The novel, highly selective CDK9 inhibitor KB-0742 was specifically designed for the treatment of patients with MYC-amplified relapsed/refractory solid tumors or non-Hodgkin lymphoma (NHL), Luo begins. The oral agent is currently under investigation in a phase 1/2 dose-escalation/expansion trial (NCT04718675) of patients with MYC-amplified or -overexpressed relapsed/refractory solid tumors, or tumors with transcription factor dysregulation. Preclinical data have demonstrated the agent’s ability to reduce off-target effects and have longer target interaction when compared with other oral CDK-targeted agents. This can be attributed to the agent’s longer half-life and increased selectivity.

Unlike other CDKs that regulate the cell cycle, CDK9 promotes the activation of target genes that control RNA polymerase II transcription, she says. As increased MYC levels are known to upregulate the transcription of RNA polymerases I to III, this is an ideal target for patients with transcriptionally-addicted tumors, Luo explains. Amplification or overexpression of the MYConcogene has been implicated as a driver of several tumor types, including subsets of non–small cell lung cancer, triple-negative breast cancer, and epithelial ovarian cancer. Other cancers with dysregulated transcription due to MYC are soft tissue sarcomas, small cell lung cancer, and NUT carcinoma, Luo adds. 

The identification of MYC amplification or overexpression in these tumors requires broad panel, next-generation sequencing, fluorescent in situ hybridization, or an immunohistochemistry assay, Luo continues. However, these tests are not routinely performed for many patients with advanced solid tumors, she notes. Therefore, it is necessary to increase the use of broad molecular diagnostics for patients with these tumor types, Luo concludes.