Targeting Super-Enhancer–Driven Transcriptional Dependencies Suppresses Aberrant Hedgehog Pathway Activation and Overcomes Smoothened Inhibitor Resistance

Article

Author: Lu, Wenjie ; Yan, Siyuan ; Mei, Yanqing ; Sui, Yi ; Jiang, Wenyan ; Zhao, Kewen ; Zhu, Ying ; Wang, Teng ; Shen, Jiayi ; Mo, Jialin ; Wang, Chaochen ; Tang, Yujie

AbstractAberrant activation of the Hedgehog (Hh) signaling pathway plays important roles in oncogenesis and therapeutic resistance in several types of cancer. The clinical application of FDA-approved Hh-targeted smoothened inhibitors (SMOi) is hindered by the emergence of primary or acquired drug resistance. Epigenetic and transcriptional-targeted therapies represent a promising direction for developing improved anti-Hh therapies. In this study, we integrated epigenetic/transcriptional-targeted small-molecule library screening with CRISPR/Cas9 knockout library screening and identified CDK9 and CDK12, two transcription elongation regulators, as therapeutic targets for antagonizing aberrant Hh activation and overcoming SMOi resistance. Inhibition of CDK9 or CDK12 potently suppressed Hh signaling and tumor growth in various SMOi responsive or resistant Hh-driven tumor models. Systemic epigenomic profiling elucidated the Hh-driven super-enhancer (SE) landscape and identified IRS1, encoding a critical component and cytoplasmic adaptor protein of the insulin-like growth factor (IGF) pathway, as an oncogenic Hh-driven SE target gene and effective therapeutic target in Hh-driven tumor models. Collectively, this study identifies SE-driven transcriptional dependencies that represent promising therapeutic vulnerabilities for suppressing the Hh pathway and overcoming SMOi resistance. As CDK9 and IRS inhibitors have already entered human clinical trials for cancer treatment, these findings provide comprehensive preclinical support for developing trials for Hh-driven cancers.Significance: Dissecting transcriptional dependencies driven by super-enhancers uncovers therapeutic targets in Hedgehog-driven cancers and identifies strategies for overcoming resistance to smoothened inhibitors.

01 May 2024·Cancer Letters

CDK inhibition results in pharmacologic BRCAness increasing sensitivity to olaparib in BRCA1-WT and olaparib resistant in Triple Negative Breast Cancer

Article

Author: Orsetti, Béatrice ; Jacot, William ; Tabet, Imene ; Sardet, Claude ; Velazquez, Carolina ; Fenou, Lise ; Rodier, Geneviève ; Theillet, Charles ; Orhan, Esin

One in three Triple Negative Breast Cancer (TNBC) is Homologous Recombination Deficient (HRD) and susceptible to respond to PARP inhibitor (PARPi), however, resistance resulting from functional HR restoration is frequent. Thus, pharmacologic approaches that induce HRD are of interest. We investigated the effectiveness of CDK-inhibition to induce HRD and increase PARPi sensitivity of TNBC cell lines and PDX models. Two CDK-inhibitors (CDKi), the broad range dinaciclib and the CDK12-specific SR-4835, strongly reduced the expression of key HR genes and impaired HR functionality, as illustrated by BRCA1 and RAD51 nuclear foci obliteration. Consequently, both CDKis showed synergism with olaparib, as well as with cisplatin and gemcitabine, in a range of TNBC cell lines and particularly in olaparib-resistant models. In vivo assays on PDX validated the efficacy of dinaciclib which increased the sensitivity to olaparib of 5/6 models, including two olaparib-resistant and one BRCA1-WT model. However, no olaparib response improvement was observed in vivo with SR-4835. These data support that the implementation of CDK-inhibitors could be effective to sensitize TNBC to olaparib as well as possibly to cisplatin or gemcitabine.

01 Jan 2024·Journal of Biological Chemistry

The reversible inhibitor SR-4835 binds Cdk12/cyclin K in a noncanonical G-loop conformation

Article

Author: Schmitz, Maximilian ; Geyer, Matthias ; Anand, Kanchan ; Roush, William R ; Moecking, Jonas ; Duckett, Derek R ; Düster, Robert ; Monastyrskyi, Andrii ; Kaltheuner, Ines H

Inhibition of cyclin-dependent kinases (CDKs) has evolved as an emerging anticancer strategy. In addition to the cell cycle-regulating CDKs, the transcriptional kinases Cdk12 and Cdk13 have become the focus of interest as they mediate a variety of functions, including the transition from transcription initiation to elongation and termination, precursor mRNA splicing, and intronic polyadenylation. Here, we determine the crystal structure of the small molecular inhibitor SR-4835 bound to the Cdk12/cyclin K complex at 2.68 Å resolution. The compound's benzimidazole moiety is embedded in a unique hydrogen bond network mediated by the kinase hinge region with flanking hydroxy groups of the Y815 and D819 side chains. Whereas the SR-4835 head group targets the adenine-binding pocket, the kinase's glycine-rich loop is shifted down toward the activation loop. Additionally, the αC-helix adopts an inward conformation, and the phosphorylated T-loop threonine interacts with all three canonical arginines, a hallmark of CDK activation that is altered in Cdk12 and Cdk13. Dose-response inhibition measurements with recombinant CMGC kinases show that SR-4835 is highly specific for Cdk12 and Cdk13 following a 10-fold lower potency for Cdk10. Whereas other CDK-targeting compounds exhibit tighter binding affinities and higher potencies for kinase inhibition, SR-4835 can be considered a selective transcription elongation antagonist. Our results provide the basis for a rational improvement of SR-4835 toward Cdk12 inhibition and a gain in selectivity over other transcription regulating CDKs.

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Indication	Highest Phase	Country/Location	Organization	Date
Triple Negative Breast Cancer	Phase 1	United States	H. Lee Moffitt Cancer Center & Research Institute, Inc.	11 Nov 2019
Glioblastoma	Preclinical	United States	Columbia University Irving Medical Center	29 Apr 2025

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