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The incredible plasticity of cancer cells: learning how to fight back!

Another story for the series “VBC PhD Students Rock”: this week in Nature Mareike Roth, from the Zuber Lab at IMP, is a co-first author on a paper that unveils a fascinating new drug resistance mechanism in leukemia, showing how cancer cells are able to rapidly adapt.

(L to R) Philipp Rathert, Johannes Zuber, Mareike Roth

Mareike Roth, a VBC PhD student in the Zuber lab at IMP is a co-first author on a paper published in Nature this week. In this paper Mareike and Philipp Rathert (the postdoc who led the project) reveal a novel mechanism behind resistance to BRD4 inhibitors in acute myeloid leukemia (AML).

The Zuber lab uses functional genetic screens to probe vulnerabilities of cancer cells, aiming to find genes that cancer cells particularly depend on, and then exploit these for the development of targeted therapies. Mareike’s PhD project is to look for such vulnerabilities among chromatin regulators, across different cancer tissues. 

“I started my PhD in 2011 in Johannes Zuber’s lab that has a general interest in identifying novel drug targets for cancer therapy. With a background in biomaterials and structural biology from my master’s studies entering the field of cancer genetics and epigenetics for my PhD was an exciting but at the same time challenging opportunity. With great support from my PhD supervisor, who had just started his lab back then, I started to pursue a few projects in various directions. However, I decided quite quickly that my main interest would be to study chromatin dependencies in cancer across different tissues.”

The story now published dates back to Zuber’s postdoc at Cold Spring Harbor Laboratory (New York), where he discovered that the gene BRD4 is an “Achilles’ heel” in leukemia. This discovery triggered a lot of excitement about BRD4 as a therapeutic target in AML and other cancers, and only four years later several BRD4 inhibitors are already being tested in clinical trials. Despite this rapid progress, it remains unclear why some cancers respond very well to these drugs, while others are resistant.  To better understand this phenomenon, Philipp and Mareike set out to identify factors that influence the response to BRD4 inhibition. 

BRD4 is a chromatin regulator that “reads” histone modifications, ultimately to promote the transcription of specific target genes. In leukemia, one particularly important BRD4 target gene is the famous MYC oncogene, whose expression can be blocked by treatment with BRD4 inhibitors.  As a first approach to better understand sensitivity and resistance to these drugs, Philipp performed a genetic screen using an shRNA library targeting chromatin regulators. The screen revealed that loss of Suz12, a core component of the Polycomb Repressive Complex (PRC2), renders AML cells resistant to BRD4 inhibition.

Philipp and Mareike then further characterized PRC2-deficient resistant cells, and found that they had restored the transcription of MYC and other BRD4 target genes, most likely through recruitment of alternative enhancer elements and compensatory signaling pathways, among them WNT signaling. When they then analyzed human leukemia cells that are “a priori” resistant, they were excited to see that these primary resistant cells exploit very similar mechanisms to rapidly compensate for the loss of BRD4. To study activity changes in enhancer elements in greater detail, Philipp and Mareike could collaborate with the Stark lab at IMP to perform STARR-seq, a revolutionary method for functional enhancer profiling.

It was really fascinating to see how the remodeling of the regulatory landscape renders some leukemia types resistant to BRD4 inhibition within in a few hours”, comments Mareike Roth.

The team also closely collaborated with colleagues at Boehringer Ingelheim in Vienna, who performed comprehensive drug sensitivity and RNA-seq analyses. In addition, Philipp and Mareike could harness an established collaboration with the group of Peter Valent at the Medical University to test whether similar resistance mechanisms occur in leukemia cells directly isolated from patients.

Taken together, the study published in Nature identifies a novel drug resistance mechanism that exploits the redundancy in cellular signaling pathways, and the ability of cells to rapidly adjust the transcriptional regulation of cancer driver genes. A better understanding of these compensatory mechanisms, which may be relevant for other chromatin-targeted agents, will not only aid the further development of BRD4 inhibitors, but may help to pinpoint targets for combinatorial therapy regimens.

We are looking forward for more exciting stories from Mareike and the Zuber Lab. All the best to Philipp, who just moved to Stuttgart in Germany to start his own lab - Congrats to Philipp, Mareike and the whole team!

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Rathert P, Roth M, Neumann T, Muerdter F, Roe JS, Muhar M, Deswal S, Cerny-Reiterer S, Peter B, Jude J, Hoffmann T, Boryn  LM, Axelsson E, Schweifer N, Tontsch-Grunt U, Dow LE, Gianni D, Pearson M, Valent P, Stark A, Kraut N, Vakoc CR and Zuber J (2015) Transcriptional plasticity promotes primary and acquired resistance to BET inhibition. Nature doi: 10.1038/nature14898 Opens external link in new windowLink