Discovery of a novel and highly selective CDK9 kinase inhibitor (JSH-009) with potent antitumor efficacy in preclinical acute myeloid leukemia models.

Acute myeloid leukemia (AML) is reported to be vulnerable to transcription disruption due to transcriptional addiction. Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, has attracted extensive attention as a drug target. Although several inhibitors, such as alvocidib and dinaciclib, have shown potent therapeutic effects in clinical trials on AML, the lack of high selectivity for CDK9 and other CDKs has limited their optimal clinical efficacy. Therefore, developing highly selective CDK9 inhibitors is still imperative for the efficacy and safety profile in treating AML. Here, we report a novel highly selective CDK9 inhibitor, JSH-009, which exhibited high potency against CDK9 and displayed great selectivity over 468 kinases/mutants. It also demonstrates impressive in vitro and in vivo antileukemic efficacy in preclinical models of AML, which makes JSH-009 a useful pharmacological tool for elucidating CDK9-mediated transcription and a novel therapeutic candidate for AML.

Aberrant accumulation of Kras-dependent pervasive transcripts during tumor progression renders cancer cells dependent on PAF1 expression.

KRAS is the most commonly mutated oncogene in human cancer, and mutant KRAS is responsible for over 90% of pancreatic ductal adenocarcinoma (PDAC), the most lethal cancer. Here, we show that RNA polymerase II-associated factor 1 complex (PAF1C) is specifically required for survival of PDAC but not normal adult pancreatic cells. We show that PAF1C maintains cancer cell genomic stability by restraining overaccumulation of enhancer RNAs (eRNAs) and promoter upstream transcripts (PROMPTs) driven by mutant Kras. Loss of PAF1C leads to cancer-specific lengthening and accumulation of pervasive transcripts on chromatin and concomitant aberrant R-loop formation and DNA damage, which, in turn, trigger cell death. We go on to demonstrate that the global transcriptional hyperactivation driven by Kras signaling during tumorigenesis underlies the specific demand for PAF1C by cancer cells. Our work provides insights into how enhancer transcription hyperactivation causes general transcription factor addiction during tumorigenesis.

Promoters of ASCL1- and NEUROD1-dependent genes are specific targets of lurbinectedin in SCLC cells.

Small-Cell Lung Cancer (SCLC) is an aggressive neuroendocrine malignancy with a poor prognosis. Here, we focus on the neuroendocrine SCLC subtypes, SCLC-A and SCLC-N, whose transcription addiction was driven by ASCL1 and NEUROD1 transcription factors which target E-box motifs to activate up to 40% of total genes, the promoters of which are maintained in a steadily open chromatin environment according to ATAC and H3K27Ac signatures. This leverage is used by the marine agent lurbinectedin, which preferentially targets the CpG islands located downstream of the transcription start site, thus arresting elongating RNAPII and promoting its degradation. This abrogates the expression of ASCL1 and NEUROD1 and of their dependent genes, such as BCL2, INSM1, MYC, and AURKA, which are responsible for relevant SCLC tumorigenic properties such as inhibition of apoptosis and cell survival, as well as for a part of its neuroendocrine features. In summary, we show how the transcription addiction of these cells becomes their Achilles's heel, and how this is effectively exploited by lurbinectedin as a novel SCLC therapeutic endeavor.

The transcriptional stress response and its implications in cancer treatment.

Cancer cells require high levels of transcription to survive and maintain their cancerous phenotype. For several years, global transcription inhibitors have been used in the treatment of cancer. However, recent advances in understanding the functioning of the basal transcription machinery and the discovery of new drugs that affect the components of this machinery have generated a new boom in the use of this type of drugs to treat cancer. Inhibiting transcription at the global level in the cell generates a stress situation in which the cancer cell responds by overexpressing hundreds of genes in response to this transcriptional stress. Many of these over-transcribed genes encode factors that may be involved in the selection of cells resistant to the treatment and with a greater degree of malignancy. In this study, we reviewed various examples of substances that inhibit global transcription, as well as their targets, that have a high potential to be used against cancer. We also analysed what kinds of genes are overexpressed in the response to transcriptional stress by different substances and finally we discuss what types of studies are necessary to understand this type of stress response to have more tools to fight cancer.

A mathematical theory of the transcription repression (TR) therapy of cancer - whether and how it may work.

Transcription repression (TR) therapy of cancer has been widely discussed. Here, TR refers to global repression of transcription rather than specific targeting of cancer-causing genes such as MYC. TR drugs inhibit transcription by binding to the transcribed DNA or to RNA polymerase; for example, actinomycin D has been extensively used in research and therapy to shut down transcription globally [1-7]. As proliferating cells demand a high rate of transcription, restricting transcript production could be effective in slowing down cell proliferation. However, TR also deprives other less proliferative cells of new transcripts, thus leading to substantial toxicity [1, 8, 9]. We now develop a mathematical theory to exploit the greater demand for transcription in highly proliferating cells. A new strategy, referred to as the TRR (transcript repression-recovery) model, would insert a recovery phase to allow the more slowly proliferating cells to recover. It is most effective to have strong blocking for a short period (a few hours) followed by a longer recovery phase in each cell cycle. Hence, TRR can potentially achieve selective killing of cells based on their global transcription needs but precise fine-tuning is necessary.