Kanazawa University Cancer Research Institute
Isozaki Lab
- Genome Biology -
Our Research Focus
This image shows a tumor phylogenetic tree that represents the evolutionary process of cancer. Mutations caused by the cytidine deaminase APOBEC tend to be observed in tree branches (late evolutionary stages).
Genomic aberrations play a crucial role in both cancer development and drug resistance. External factors such as ultraviolet radiation, smoking, drugs, viral infections, and aging contribute to the accumulation of somatic mutations in the nuclear DNA of a single cell, ultimately leading to carcinogenesis and treatment resistance. This process, known as clonal evolution, reflects the increasing heterogeneity of cancer genomes over time. While the mechanisms underlying the induction of somatic mutations are not yet fully understood, several factors have been identified, one of which is APOBEC, a cytidine deaminase enzyme. APOBEC deaminates cytidine at the TpC motif in DNA and RNA, converting it to uridine.
In our recent study, we discovered that molecular-targeted therapies induce APOBEC3A. The therapy-induced APOBEC3A increases genomic instability by generating somatic mutations and chromosomal abnormalities, which drive the evolution of drug-resistant clones and contribute to treatment failure. These findings suggest that inhibiting APOBEC3A could be a promising therapeutic strategy to prevent acquired resistance (Isozaki et al., Nature 2023). Following this report, the development of new therapies targeting APOBEC3A is now highly anticipated (Villanueva, Nat Rev Drug Discov. 2023).
The Isozaki Lab is focused on developing inhibitors of APOBEC3A and uncovering the detailed mechanisms of clonal evolution to establish novel therapeutic strategies that can prevent carcinogenesis and drug resistance. Additionally, we aim to pioneer new cancer treatments by leveraging genome editing technologies.
Resistance to
lung cancer therapy
Efficacy of ALK TKI
(e.g. Crizotinib)
61yr female
EML4-ALK
NSCLC
T4N3M1
Day3
Day6
Day24
Preural effusion was collected before treatment
Cells were injected subcterneously
Patient delivered cells line
Xenograft mouse model
Study using patient derived models
Lung cancer ranks first in both cancer incidence and mortality rates in a survey of 185 countries around the world and is an important issue that needs to be solved on a global scale (WHO/IARC 2024).
Tyrosine kinase inhibitors (TKIs), which target epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), are the most effective treatment for advanced non-small cell lung cancers harboring mutated EGFR or ALK fusion genes. However, in almost all cases, tumors develop resistance to TKIs and relapse. Overcoming acquired resistance and developing permanently effective drugs could significantly reduce lung cancer mortality.
Although effective treatment diminishes many cancer cells, some cells can survive during therapy, so-called drug-resistant cells (DTPs). Drug-resistant cells are a population that has evolved from DTPs (Hata et al., Nature Med 2016). We believe that eliminating DTPs can prevent acquired drug resistance.
Our laboratory aims to elucidate the DTP evolutionary process by focusing on the innate immunity in DTPs and develop new therapeutic agents that inhibit DTP evolution.
APOBECs
and
Tumor Evolution
Tumor DNA derived from a patient with non-small cell lung cancer was analyzed. Higher mutation burden was observed in post treatment tumors. Mutational signature analysis revealed that majority of mutations were attributed to APOBEC which is one of the innate immune factors.
Apolipoprotein B mRNA editing enzyme catalytic polypeptide (APOBEC), a prominent mutator that converts cytidine to uridine in the TpC motif of DNA or RNA, is thought to be involved in cancer development based on analysis of genetic mutation patterns in patient tumors. In a study of 100 early-stage non-small cell lung cancer (NSCLC) tumors that were resected before treatment, the number of subclonal mutations was significantly correlated with the number of genetic mutations caused by APOBECs, suggesting that APOBECs contribute to clonal evolution (Jamal-Hanjani et al., NEJM 2017).
For example, AID and APOBEC3 deaminate DNA and activate the innate immune system. APOBEC1 participates in lipid transport by mediating apolipoprotein B RNA editing. APOBEC has been considered to be a hallmark of evolution, as more APOBEC family members have been observed with biological evolution.
In a recent study, we revealed that APOBEC3A promotes the evolution of DTPs by increasing their genomic instability, leading to drug resistance. Furthermore, inhibition of APOBEC3A could delay acquired resistance (Isozaki et al., Nature 2023). Our laboratory aims to develop oligonucleotide therapeutics targeting APOBEC3A and elucidate the regulatory mechanism of APOBEC3A. We also investigate the impact of APOBEC3A on the development of hereditary breast cancer.