Reference Detail

Ref Type

Journal Article

PMID

(36398965)

Authors

Malone CF, Kim M, Alexe G, Engel K, Forman AB, Robichaud A, Conway AS, Goodale A, Meyer A, Khalid D, Thayakumar A, Hatcher JM, Gray NS, Piccioni F, Stegmaier K

Title

Transcriptional Antagonism by CDK8 Inhibition Improves Therapeutic Efficacy of MEK Inhibitors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	83	2	2023 Jan 18	285-300	Cancer Res

URL

Abstract Text

Aberrant RAS/MAPK signaling is a common driver of oncogenesis that can be therapeutically targeted with clinically approved MEK inhibitors. Disease progression on single-agent MEK inhibitors is common, however, and combination therapies are typically required to achieve significant clinical benefit in advanced cancers. Here we focused on identifying MEK inhibitor-based combination therapies in neuroblastoma with mutations that activate the RAS/MAPK signaling pathway, which are rare at diagnosis but frequent in relapsed neuroblastoma. A genome-scale CRISPR-Cas9 functional genomic screen was deployed to identify genes that when knocked out sensitize RAS-mutant neuroblastoma to MEK inhibition. Loss of either CCNC or CDK8, two members of the mediator kinase module, sensitized neuroblastoma to MEK inhibition. Furthermore, small-molecule kinase inhibitors of CDK8 improved response to MEK inhibitors in vitro and in vivo in RAS-mutant neuroblastoma and other adult solid tumors. Transcriptional profiling revealed that loss of CDK8 or CCNC antagonized the transcriptional signature induced by MEK inhibition. When combined, loss of CDK8 or CCNC prevented the compensatory upregulation of progrowth gene expression induced by MEK inhibition. These findings propose a new therapeutic combination for RAS-mutant neuroblastoma and may have clinical relevance for other RAS-driven malignancies.Transcriptional adaptation to MEK inhibition is mediated by CDK8 and can be blocked by the addition of CDK8 inhibitors to improve response to MEK inhibitors in RAS-mutant neuroblastoma, a clinically challenging disease.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
BI-1347	BI-1347	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
BI-1347		BI1347\|BI 1347	CDK8 Inhibitor 5	BI-1347 inhibits CDK8 and CDK19, which leads to reduced levels of phosphorylated Stat1 and increased activity of NK cells, potentially resulting in tumor growth inhibition, in combination with other agents (PMID: 32024684, PMID: 36398965).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
NRAS Q61K	neuroblastoma	sensitive	BI-1347 + Selumetinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of BI-1347 and Koselugo (selumetinib) resulted in reduced tumor growth and improved survival compared to Koselugo (selumetinib) alone in a neuroblastoma cell line xenograft model harboring NRAS Q61K (PMID: 36398965).	36398965
NRAS Q61K	neuroblastoma	sensitive	BI-1347 + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of BI-1347 to Mekinist (trametinib) resulted in enhanced growth inhibition of a neuroblastoma cell line harboring NRAS Q61K compared to Mekinist (trametinib) alone in culture (PMID: 36398965).	36398965