1. Samson, Kurt

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Preclinical experiments have identified a key transcription factor as a potential therapeutic target for treating pancreatic cancer, researchers shared at the 2021 Annual Meeting of the American Association for Cancer Research (AACR).

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Mutant KRAS and p53, the most frequently mutated genes in pancreatic cancer, interact through the CREB1 protein to promote metastasis and tumor growth. Blocking CREB1 in preclinical models reversed these effects and reduced metastases, suggesting an important new therapeutic target for the deadly cancer, Michael Kim, MD, Assistant Professor in the Department of Surgical Oncology at The University of Texas MD Anderson Cancer Center, told a pre-conference press briefing.


Pancreatic ductal adenocarcinoma (PDAC) is almost uniformly fatal and characterized by early metastasis, he noted. Oncogenic KRAS mutations prevail in 95 percent of PDAC tumors and co-occur with genetic alterations in the TP53 tumor suppressor in nearly 70 percent of patients.

Michael Kim, MD. Mic... - Click to enlarge in new windowMichael Kim, MD. Michael Kim, MD

"Pancreatic cancer is frequently diagnosed after the disease has metastasized, resulting in limited treatment options and subsequent high mortality rates," Kim said. "Identifying new therapeutic targets for this deadly cancer represents an urgent unmet need in the field of oncology."


To understand the relationship between the two cancer driver genes, Kim and his colleagues first genetically engineered a mouse model of PDAC that expressed both oncogenic KRAS and mutant p53 specifically in pancreas tumor cells, but did not disturb immune cells or fibroblasts within the tumor microenvironment.


Using this model, along with pancreatic tumors derived from human patients, the researchers found that effectors of oncogenic KRAS activate CREB1, which then interacts with mutant p53 to upregulate the transcription factor FOXA1. This then activates pro-metastatic transcriptional signals that facilitate pancreatic cancer metastasis, Kim explained.


The team next evaluated whether inhibiting CREB1 would affect FOXA1 expression and subsequent pancreatic cancer metastasis. They treated pancreatic cancer cells with a potent and selective CREB1 inhibitor and found a dose-dependent reduction in both the expression of FOXA1 and its downstream effector.


Mice injected with pancreatic cancer cells then revealed that those treated with the CREB1 inhibitor had significantly fewer lung metastases than those treated with the inhibitor. The incidence of metastatic lesions in the liver and lungs of control mice was more than twofold greater than in treated animals.


"To our knowledge, this is the first study to show how these two major genetic drivers work together to promote tumor growth and metastasis," Kim said. "We learned that signaling downstream of mutant KRAS directly promotes mutant p53 activity. This discovery provides not only a new therapeutic target but unveils a vast transcriptional network that is activated downstream of these mutant proteins."


Cascade of Changes

Mutations in KRAS and TP53, the two most frequently mutated genes in all human cancers, co-occur in roughly 70 percent of patients with pancreatic cancer. Mutant KRAS is found in 95 percent of pancreatic cancers and leads to an activated protein that aberrantly triggers many downstream signaling pathways. Mutant TP53 results in the loss of the proteins' tumor suppressor function, leaving the mutant protein capable of enabling additional oncogenic processes, including metastasis.


There are currently no therapies that can block the mutant forms of KRAS or P53 prevalent in pancreatic cancer, so there is a need to identify common, alternative therapeutic targets downstream of these proteins that could lead to more effective treatment regimens for pancreatic cancer, Kim said.


"The goal of our study was to find a link between these two genetic drivers of pancreatic cancer to better understand how they work together to drive tumor growth and metastasis," he noted.


"Through our work, we've shown how two cancer driver pathways can cooperate to amplify myriad downstream targets that are important for pancreatic cancer development and metastasis. We've identified a targetable, cooperative node between these driver pathways that might be therapeutically exploited to improve patient outcomes."


Mutations in KRAS and P53 are common in many other cancer types in addition to pancreatic cancer.


In this model, the team observed more than twice as many metastatic lesions than was seen when P53 was genetically removed, suggesting that the mutant proteins together cause a significant increase in metastatic potential. With further study, the researchers discovered mutant KRAS activates CREB1, a transcription factor that then directly interacts with mutant p53 to promote the aberrant expression of hundreds of genes.


This activation results in the increased expression of FOXA1, which in turns creates a new cascade of events leading to increased activity of the Wnt/[beta]-catenin pathway, both of which promote cancer metastasis.


Using an available small-molecule drug to target CREB1 in this model resulted in decreased expression of FOXA1, [beta]-catenin and associated target genes, along with a corresponding reduction in metastases. While early, these findings suggest that targeting CREB1 may be a viable strategy to block the metastatic effects of mutant KRAS and p53 in pancreatic cancer.


"Our findings demonstrate a direct, mechanistic link between key oncogenic KRAS signaling elements and mutant P53 that result in a broad, multiplexed activation of cancer-associated transcriptional networks. Moreover, we identify CREB1 as a viable therapeutic strategy to undermine oncogenic KRAS and mutant p53 cooperation to mitigate PDAC metastasis," Kim explained.


"The identification of this cooperative node suggests that there should be increased focus on CREB1 as a target that could be therapeutically exploited to improve patient outcomes," he said. "With the frequency of KRAS and TP53 mutations in human cancers, the implications of our findings may extend far beyond pancreatic cancer."


Going forward, the researchers hope to discover other important elements working downstream of mutant p53 that may affect the cancer cells or the surrounding tumor microenvironment. A greater understanding of this complex network may point to additional therapeutic targets or combination approaches to better treat pancreatic cancer.


"We hope that our study will generate increased interest in CREB1 as a therapeutic target and the subsequent development of additional CREB1 inhibitors, which could potentially be used to treat multiple cancer types," Kim stated.


A limitation of the study is its preclinical nature, he added. "Further research is needed to evaluate the safety of CREB1 inhibitors in patients to translate the findings of our study to patients with pancreatic cancer."


Kurt Samson is a contributing writer.