Functionalizing the genome to find novel pancreatic cancer treatments

From the Kemp Lab, Human Biology Division

Taped outside of the lab of Dr. Christopher Kemp, a professor in the Human Biology Division, hangs a piece of paper with an earlier version of the Fred Hutch logo- a DNA helix integrated between an “H” with the slogan, “Advancing Knowledge, Saving Lives”. Russell Moser, a research scientist in the Kemp Lab explains that this serves as motivation for his own research using functional genetic approaches to identify new ways to target RAS-driven cancers. One RAS-driven cancer that has been particularly challenging to treat is pancreatic ductal adenocarcinoma (PDAC). These cancers often are driven by co-mutations in KRAS and tumor suppressor p53 and typically present as metastatic by the time of diagnoses in 80% of patients. PDAC is a leading cause of cancer death, however patient survival and treatments have not improved substantially over the past several decades. In a recent Cancer Research study led by Moser, the Kemp team took an unbiased functional precision medicine approach to identify novel PDAC targets and therapeutic strategies.   

In collaboration with Dr. Dan Von Hoff of the TGEN Institute, the researchers first developed a PDAC patient-derived xenograft model following surgical removal of the tumor. Notably, the treatment of this pancreatic cancer patient ultimately failed and the patient died within a year, highlighting the aggressiveness of this cancer and dire need for better treatment options. The Kemp team then took these patient-derived PDAC cells and performed whole-exome sequencing to identify mutations, as well as a genome -scale siRNA screen to pinpoint genetic dependencies, in parallel with drug profiling to identify potential therapeutic strategies. Whole-exome sequencing of these PDAC cells identified 117 mutations in the coding region of genes, most notably an activating G12V mutation in the oncogene KRAS  and a truncating mutation in the tumor suppressor p53 (TP53).  As is the case for most cancers, this genomic characterization was insufficient to point to potential therapies, so the researchers turned to functional genetics, where they performed an unbiased functional genomic screen with a highly comprehensive RNAi library to knockdown ~6,700 target genes in order to find potential driver mutations and new cancer vulnerabilities. Importantly, many of these had “druggable signaling nodes” which enabled the researchers to validate these targets  as therapeutic strategies. “One of the most exciting parts about this study was the sheer list of novel targets we found, too much for one lab to follow up on” Kemp stated. The researchers sought out targets that had selective lethality when knocked down in PDAC patient cells compared to patient-derived non-cancerous pancreatic cells.

Overview of functional genetic approach for identifying pancreatic cancer targets and therapeutic strategies.
Overview of functional genetic approach for identifying pancreatic cancer targets and therapeutic strategies. Image taken from original article.

Functional genomic and drug profiling of PDAC patient-derived cell cultures and organoids converged to identify the CDK7 transcriptional kinase and the ERCC3 subunits of TFIIH, the general transcription and DNA repair factor complex, and CFLAR, the CASP8 and FADD like apoptosis regulator, as robust KRAS mutant PDAC dependencies. Furthermore, TFIIH inhibition with various compounds led to transcriptional downregulation of CFLAR and synergized with TRAIL (TNF-related apoptosis inducing ligand) to selectively kill  pancreatic cancer cells via death receptor-mediated apoptosis. This synergistic effect was widespread across 10 out of 11 KRAS mutant patient-derived PDAC cell lines test. This work emphasizes how the TRAIL system and CFLAR which regulates the extrinsic apoptotic pathway “is an important vulnerability in KRAS mutant PDAC that could be exploited therapeutically especially in combination with TFIIH inhibitors (CDK7/XPB),” Moser notes. Currently, next-generation hexavalent TRAIL agonists, and the TFIIH inhibitor triptolide are in Phase II clinical trials, but currently not being tested in combination for KRAS mutant PDAC, which demonstrates the feasibility of pushing these drugs towards testing in PDAC patients.

Kemp explains that he is enthusiastic about pushing this research into clinic and Dr. Von Hoff is actively pursuing a clinical trial based on these findings. Future efforts to advance PDAC treatment will focus on further elucidating the TRAIL system(s) and apoptotic/autophagic pathways in KRAS mutant pancreatic ductal adenocarcinoma in addition to investigating DNA damage and repair pathways, specifically the transcription-coupled nucleotide excision repair (TC-NER) in the context of first-line therapies for PDAC. Moser concludes by stating, “The cancer community should be optimistic that functional genomics and pharmacological screening approaches of patient-derived tumor models can identify new targets and effective drugs to better inform clinical treatment and will play an important role in precision medicine.”

This work was supported by the National Institutes of Health, the National Cancer Institute, the American Cancer Society, the National Foundation for Cancer Research, Canary Foundation, Listwin Foundation, and Gregory Fund, the Seena Magovitz Foundation, Lee T. Hanley Fund for Pancreatic Cancer Research, and a Stand Up To Cancer-Cancer Research UK-Lustgarten Foundation.

Fred Hutch/UW Cancer Consortium member Christopher Kemp contributed to this work.

Moser R, Annis J, Nikolova O, Whatcott C, Gurley K, Mendez E, Moran-Jones K, Dorrell C, Sears RC, Kuo C, Han H, Biankin A, Grandori C, Von Hoff DD, Kemp CJ. Pharmacologic Targeting of TFIIH Suppresses KRAS-Mutant Pancreatic Ductal Adenocarcinoma and Synergizes with TRAIL. Cancer Res. 2022 Sep 16;82(18):3375-3393. doi: 10.1158/0008-5472.CAN-21-4222. PMID: 35819261; PMCID: PMC9481717.