Background

Pancreatic cancer is classified as a representative refractory cancer with a 5-year survival rate of around 10%. More than 90% of patients are found to have RAS gene mutations, which are cancer-causing genes. However, for a long time, this protein has been an area where targeted drug development has been impossible due to its structural characteristics that make it difficult for drugs to bind. Fortunately, the emergence of daraxonrasib, a new drug that selectively inhibits activated RAS mutant proteins, is expected to be a new milestone in the treatment of pancreatic cancer. In a clinical study of patients with advanced pancreatic cancer, this drug extended the survival period of patients compared to existing chemotherapy.

However, in cancer treatment using targeted drugs, the occurrence of drug resistance is an unavoidable obstacle. Tumor cells in patients who have been administered daraxonrasib for a long time eventually find a bypass pathway to neutralize the drug's effect and resume proliferation. In order to fully benefit from the therapeutic benefits of the new drug and maximize survival, it was necessary to clearly identify the genetic changes that cause drug resistance.

This study is significant in that it analyzed the patient's clinical samples to reveal the cause of daraxonrasib resistance at the gene level.

Key Findings

A study published in the international journal Nature Medicine revealed that the researchers compared cell-free DNA (cfDNA) extracted from the blood of pancreatic cancer patients with disease progression during daraxonrasib treatment and tumor biopsy tissues before and after treatment. In this process, three major genetic mutations that induce acquired resistance to daraxonrasib were identified.

The first cause is a structural change in the drug-binding site. Daraxonrasib forms a triple complex by binding to cyclophilin A (CypA), an intracellular protein, thereby blocking the action of activated RAS. As a result of the analysis, a mutation (Y64H or Y64N) was found in some resistant tumors, in which the 64th amino acid, tyrosine, of the RAS protein is replaced with another amino acid. This mutation was found to impair the space where the drug binds to CypA, reducing the binding affinity of daraxonrasib by more than 80% compared to the original.

The second mechanism is the amplification phenomenon due to an increase in the copy number of target genes. Cells that have developed drug resistance increased the copy number of mutated KRAS genes on their own to offset the drug's effect. As a result, the target protein is abnormally increased, resulting in the drug not being able to completely block intracellular signal transduction.

The third is the activation of upstream and downstream signal transduction bypass pathways. The researchers confirmed that the epidermal growth factor receptor (EGFR) signaling system was excessively activated in resistant cells. In addition, they revealed that a loss-of-function mutation occurred in the BRAF gene, a downstream protein, which induced the formation of RAF protein dimers. This results in the continued activation of downstream growth signals regardless of whether the RAS protein is inhibited.

In order to overcome these resistance mechanisms, the researchers verified the possibility of combination therapy in an animal model. When daraxonrasib was administered alone, the tumor regrew within a few weeks, but when afatinib, an EGFR inhibitor that blocks the bypass pathway, was administered together, the growth of cancer cells was continuously inhibited. This treatment combination showed excellent anti-cancer effects, with significant tumor regression.

Significance and Prospects

This discovery has established a scientific milestone in overcoming the limitations of daraxonrasib treatment. By clearly defining the resistance mechanism, a foundation has been laid for providing personalized follow-up treatment to patients using pan-RAS inhibitors in the future. In particular, it has demonstrated the possibility of realizing precision medicine by proactively diagnosing the resistance profile of patients using liquid biopsy technology and prescribing the next-generation combination therapy that matches it.

However, there are challenges to be solved before it can be applied in clinical practice. This is because the type and combination of gene mutations that induce resistance vary from patient to patient. Therefore, instead of a uniform combination therapy, there is a clinical challenge to design a patient-specific treatment combination in real time. Concerns about side effects and systemic toxicity when inhibiting multiple targets are also issues to be solved in additional human clinical trials. The researchers plan to conduct an early clinical study in the future to establish a safe combination dose of daraxonrasib and various signal blockers in patients with pancreatic cancer.