Pancreatic cancer is a highly malignant tumor of the digestive tract that is difficult to diagnose and treat. 90% of the subtypes are pancreatic ductal adenocarcinoma (PDAC).

In recent years, the incidence and mortality of pancreatic cancer have increased significantly. The early diagnosis rate of pancreatic cancer is poor, which is often at an advanced stage when discovered, when cancer cells have spread, and is difficult to treat. The 5-year survival rate is less than 7%.

About 50% of patients with PDAC will develop distant metastases that often occur in the early stages and is the result of complex interactions between tumor cell autonomous processes and cellular components in the tumor microenvironment.

The oncogene KRAS ( promotes the occurrence of tumors, and the inactivation of related key tumor suppressor genes accelerates the malignant progression of pancreatic intraepithelial neoplasia (PanIN) precursor lesions. Approximately 70% of PDAC patients have p53 gene mutations, and approximately 90% of PDAC patients have KRAS gene mutations. The common phenomenon of KRAS and p53 co-mutation in PDAC patients suggests that there is a potential synergistic mechanism that drives tumor development and metastasis that has yet to be elucidated. An in-depth understanding of the complex interaction between mutant KRAS and mutant p53 will help develop therapies to reverse the malignant progression of tumors.

On April 10, 2021, Michael P. Kim of MD Anderson Cancer Center published a research paper titled Oncogenic KRAS recruits an expansive transcriptional network through mutant p53 to drive pancreatic cancer metastasis in Cancer Discovery. The study shows that mutant KRAS and mutant p53 interact with each other by CREB1 protein to promote the growth and metastasis of pancreatic cancer, which further reveals that blocking CREB1 in preclinical models can reverse such effects and reduce pancreatic cancer metastasis, providing a new therapeutic target.

It is reported that this is also the first study to show how the two main genetic drivers, mutant KRAS and mutant p53, can jointly promote tumor growth and metastasis.

In this study, the degree of direct cooperation between KRAS and mutant p53 was explored in order to find a new therapeutic strategy to slow cancer progression and metastasis. In order to express the mutant p53R172H (corresponding to the human p53R175H hotspot mutation) only in PDAC while retaining the wild-type p53 function in all mesenchymal cells, the research team constructed LSL- KrasG12D, p53wmR172H/+, and Pdx1-Cre (KPwm/+C) mouse models, which exhibit the characteristics of tumor aggressiveness and metastasis, indicating that the mutation p53R172H significantly increases PDAC metastasis in vivo.

Next, the research team used flow cytometry, RNA-seq, and TFBS computing systems to detect the up-regulated gene promoters in the mutant p53R172H tumors and found that the mutant p53 tumors were related to the transcriptional characteristics of FOXA1. The human PDAC TCGA data set was used to compare the expression of FOXA1 in normal pancreas and PDAC tumors, and it was found that the average expression value of FOXA1 in PDAC patients increased by 7 times, indicating that it is generally up-regulated in pancreatic cancer and is related to prognosis.

In order to understand how the mutant p53 interacts with the transcription complex at the FOXA1 promoter to drive its expression, the research team conducted genetic and pharmacological inhibition, luciferase double reporting and immunoprecipitation, and ChIP qPCR experiments in a group of mouse and human PDAC cell lines, and found that oncogenic KRAS mainly mediated CREB1S133 phosphorylation, and activated CREB1 can enhance the binding of mutant p53 and FOXA1 promoter, leading to activation of the transcription network, and meanwhile promoting Wnt/β-catenin signal transduction, which together drove PDAC transfer.

In summary, this study details a new molecular mechanism of pancreatic cancer metastasis, namely, the acquisition of function by mutant p53 to drive PDAC metastasis, which is conditioned by the phosphorylation of CREB1S133, and mainly mediated through the oncogenic KRAS-RAF-MEK-MAPK pathway. Drug inhibition of CREB1 significantly reduced the expression of FOXA1 and β-catenin, and inhibited PDAC metastasis, providing a new treatment strategy to disrupt the interaction between mutant KRAS and mutant p53 to delay cancer progression and metastasis.

Single-domain antibodies (sdAbs), not only have the specific antigen recognition capabilities of conventional monoclonal antibodies, but also possess unique advantages and uses due to their small molecular scale and simple structure.

Currently, there are a variety of immunotherapy strategies for pancreatic cancer, including specific and non-specific immunotherapy, tumor vaccines, adoptive immune cell therapy, and tumor factor therapy.

Targeted drugs
1. EGFR targets: Erlotinib, Cetuximab (Aipito), Gefitinib
2. HER2 target: trastuzumab
3. MAPK antibody: Trametinib combined with EGFR antibody ( and HER2 antibody can increase its efficiency in inhibiting the proliferation of pancreatic cancer cells. The mechanism may be through inhibition of MAPK signaling pathway and feedback activation of tyrosine kinase signaling pathway.
4. mTOR inhibitors: everolimus, temsirolimus
5. IGF-IR inhibitor: Ruzotinib combined with capecitabine
6. JAK inhibitor
7. VEGF, anti-angiogenic drugs
8. Endostatin
9. MMPs inhibitor
10. DNA topoisomerase I inhibitor
11. Inhibit microRNAs (microRNAs, miRNA)

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