Bjoern Papke

• PhD
• PostDoc Position at University of North Carolina at Chapel Hill

The three RAS oncogenes make up the most frequently mutated gene family in human cancer. The well-validated role of mutationally activated RAS genes in driving cancer development and growth has stimulated comprehensive efforts to develop therapeutic strategies to block mutant RAS function for cancer treatment. Disappointingly, despite more than thr...

The KRAS oncogene product is considered a major target in anticancer drug discovery. However, direct interference with KRAS signalling has not yet led to clinically useful drugs. Correct localization and signalling by farnesylated KRAS is regulated by the prenyl-binding protein PDEδ, which sustains the spatial organization of KRAS by facilitating i...

The prenyl-binding protein PDE is crucial for the plasma membrane localization of prenylated Ras. Recently, we have reported that the small-molecule Deltarasin binds to the prenyl-binding pocket of PDE, and impairs Ras enrichment at the plasma membrane, thereby affecting the proliferation of KRas-dependent human pancreatic ductal adenocarcinoma cel...

KRas is a major proto-oncogene product whose signaling activity depends on its level of enrichment on the plasma membrane (PM). This PM localization relies on posttranslational prenylation for membrane affinity, while PM specificity has been attributed to electrostatic interactions between negatively charged phospholipids in the PM and basic amino-...

Ras or Rat sarcoma is a central node in signal transduction networks that includes a range of oncogenic proteins in its family. These small guanine nucleotide-binding proteins transmit signals from lipid membranes in the cell with which they interact by an acquired affinity through posttranslational modifications at their C-terminal hypervariable r...

Secondary resistance limits the clinical effectiveness of mutation-specific RAS inhibitors in colorectal cancer. It is unknown whether broad-spectrum RAS inhibitors meet similar limitations. Here, we identify and categorize mechanisms of resistance to the broad-spectrum active-state RAS inhibitor RMC-7977 in colorectal cancer cell lines. We found t...

Mutational loss of CDKN2A (encoding p16INK4A) tumor-suppressor function is a key genetic step that complements activation of KRAS in promoting the development and malignant growth of pancreatic ductal adenocarcinoma (PDAC). However, pharmacologic restoration of p16INK4A function with inhibitors of CDK4 and CDK6 (CDK4/6) has shown limited clinical e...

The aggressive nature of pancreatic ductal adenocarcinoma (PDAC) mandates the development of improved therapies. As KRAS mutations are found in 95% of PDAC and are critical for tumor maintenance, one promising strategy involves exploiting KRAS-dependent metabolic perturbations. The macrometabolic process of autophagy is upregulated in KRAS-mutant P...

We apply genetic screens to delineate modulators of KRAS mutant pancreatic ductal adenocarcinoma (PDAC) sensitivity to ERK inhibitor treatment, and we identify components of the ATR-CHK1 DNA damage repair (DDR) pathway. Pharmacologic inhibition of CHK1 alone causes apoptotic growth suppression of both PDAC cell lines and organoids, which correlates...

Oncogenic KRAS drives cancer growth by activating diverse signaling networks, not all of which have been fully delineated. We set out to establish a system-wide profile of the KRAS-regulated kinase signaling network (kinome) in KRAS-mutant pancreatic ductal adenocarcinoma (PDAC). We knocked down KRAS expression in a panel of six cell lines, and the...

To identify therapeutic targets for KRAS mutant pancreatic cancer, we conduct a druggable genome small interfering RNA (siRNA) screen and determine that suppression of BCAR1 sensitizes pancreatic cancer cells to ERK inhibition. Integrative analysis of genome-scale CRISPR-Cas9 screens also identify BCAR1 as a top synthetic lethal interactor with mut...

Oncogenic KRAS drives cancer growth by activating diverse signaling networks, not all of which have been fully delineated. We set out to establish a system-wide profile of the KRAS-regulated kinase signaling network (kinome) in KRAS-mutant pancreatic ductal adenocarcinoma (PDAC). We knocked down KRAS expression in a panel of six cell lines, and the...

Oncogenic mutations in the KRAS gene are well-established drivers of cancer. While the recently developed KRASG12C inhibitors offer a targeted KRAS therapy and have shown success in the clinic, KRASG12C represents only 11% of all KRAS mutations. Current therapeutic approaches for all other KRAS mutations are both indirect and nonmutant-selective, l...

Oncogenic mutations in the KRAS gene are well-established drivers of cancer. While the recently developed KRAS G12C inhibitors offer a targeted KRAS therapy and have shown success in the clinic, KRAS G12C represents only 11% of all KRAS mutations. Current therapeutic approaches for all other KRAS mutations are both indirect and non-mutant-selective...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

We address whether combinations with a pan-RAF inhibitor (RAFi) would be effective in KRAS mutant pancreatic ductal adenocarcinoma (PDAC). Chemical library and CRISPR genetic screens identify combinations causing apoptotic anti-tumor activity. The most potent combination, concurrent inhibition of RAF (RAFi) and ERK (ERKi), is highly synergistic at...

Oncogenic mutations in the KRAS gene are well-established drivers of cancer. Promising preclinical strategies including RNA interference (RNAi) have been developed to target oncogenic KRAS function, yet a clinically effective therapy to directly target KRAS remains to be achieved. While genetic knockdown of mutant KRAS (mKRAS) with RNAi is one prom...

Allele-specific signaling by different KRAS alleles remains poorly understood. The KRASG12R mutation displays uneven prevalence among cancers that harbor the highest occurrence of KRAS mutations: It is rare (∼1%) in lung and colorectal cancers, yet relatively common (∼20%) in pancreatic ductal adenocarcinoma (PDAC), suggesting context-specific prop...

Pancreatic ductal adenocarcinoma (PDAC) patients have a dismal five-year survival rate of just eight percent in the advanced metastatic setting. Outcomes with standard chemotherapy regimens are less than ideal; therefore, the development of targeted therapies for the treatment of PDAC is a significant unmet clinical need. The two most frequent gene...

Pancreatic ductal adenocarcinoma (PDAC) patients have a dismal five-year survival rate of just eight percent in the advanced metastatic setting. Outcomes with standard chemotherapy regimens are less than ideal; therefore, the development of targeted therapies for the treatment of PDAC is a significant unmet clinical need. The two most frequent gene...

Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS- and autophagy-dependent tumorigenic growth, but the role of KRAS in supporting autophagy has not been established. We show that, to our surprise, suppression of KRAS increased autophagic flux, as did pharmacological inhibition of its effector ERK MAPK. Furthermore, we demonstrate tha...

72 hour life cell imaging of Panc-Tu-I cells treated with 5 μM Deltarasin immediately before the beginning of the movie.

72 hour life cell imaging of Panc-Tu-I cells treated with 10 μM Deltazinone 1 immediately before the beginning of the movie.

72 hour life cell imaging of PANC-1 cells treated with DMSO immediately before the beginning of the movie. Each frame represents one hour

Supplementary Figures 1-5, Supplementary Tables 1-4, Supplementary Methods and Supplementary References

72 hour life cell imaging of Panc-Tu-I cells treated with DMSO immediately before the beginning of the movie. Each frame represents one hour.

72 hour life cell imaging of PANC-1 cells treated with 5 μM Deltarasin immediately before the beginning of the movie.

72 hour life cell imaging of PANC-1cells treated with 10 μM Deltazinone 1 immediately before the beginning of the movie.

The localization and signaling of S-palmitoylated peripheral membrane proteins is sustained by an acylation cycle in which acyl protein thioesterases (APTs) depalmitoylate mislocalized palmitoylated proteins on endomembranes. However, the APTs are themselves reversibly S-palmitoylated, which localizes thioesterase activity to the site of the antago...

Precise quantification of endogenous protein-protein interactions across live cells would be a major boon to biology. Such precise measurement is theoretically possible with fluorescence lifetime imaging microscopy (FLIM) but requires first properly addressing multiple biological, instrumental, statistical, and photophysical challenges. We present...