The Super Elongation Complex May Be Targetable in MYC-Driven Tumors

The super elongation complex (SEC) is essential for the release of promoter-proximal pausing, allowing productive transcription of RNA polymerase II (Pol II)–transcribed genes. The positive transcription elongation factor b (P-TEFb) is primarily sequestered in an inactive form, but can interact with SEC or with BRD4 in active complexes. Although BRD4 inhibitors exist to target the BRD4/P-TEFb complex, specific inhibitors of P-TEFb in the SEC are lacking, prompting Liang and colleagues to seek to identify small-molecule SEC disrupters. Two peptidomimetic lead compounds were discovered, KL-1 and KL-2, which blocked the interaction between P-TEFb and the SEC scaffolding protein AFF4 to disrupt SEC function. These small-molecule inhibitors increased promoter-proximal pausing at the early stage of transcription elongation and slowed down Pol II transcription elongation. KL-1 and KL-2 treatment reduced SEC-mediated induction of heat shock gene transcription, impairing the heat shock response. Further, KL-1 and KL-2 treatment reduced expression of MYC and MYC target genes, and chromatin immunoprecipitation sequencing revealed that MYC-high cancer cells had increased co-occupancy of MYC and SEC genome-wide, suggesting the potential for therapeutic targeting of SEC in MYC-driven cancer cells. In vivo, KL-1/KL-2 treatment delayed tumor progression and extended survival in a MYC-dependent breast tumor model without apparent toxicity. Taken together, these findings indicate that the SEC complex may be a therapeutic target in MYC-dependent tumors, supporting further clinical development of small-molecule SEC disruptors.

Liang K, Smith ER, Aoi Y, Stoltz KL, Katagi H, Woodfin AR, et al. Targeting processive transcription elongation via SEC disruption for MYC-induced cancer therapy. Cell 2018;175:766–79.e17.

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