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Cancer Therapeutics

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Current precision medicine strategies for human cancers target activated proteins such as the tyrosine kinases EGFR, BRAF, and ALK-fusion; these proteins are activated by gain-of-function (GOF) genetic aberrations including gene mutation, amplification, and fusion. Activated oncogenes constitute a specific vulnerability of cancer cells. Inhibition of the synthesis or activity of these oncogenes results in cell death, specifically in cells expressing the activated oncogene; the dependence of cells on an oncogene for survival is defined as “oncogene addiction” . Only a fraction of cancers have an activated oncogene, whereas many cancers have other genetic aberrations such as loss-of-function (LOF) mutations. Certain LOF gene mutations of tumor suppressor genes confer druggable vulnerabilities on cancer cells. However, because genes with LOF mutations are inactivated, the LOF mutation gene product is not a target for inhibition. Harnessing synthetic lethality has emerged as an attractive therapeutic strategy based on LOF mutations, although that has remained elusive. Precision medicine for cancers with a LOF gene is feasible through the inhibition of the LOF mutation gene product as a synthetic lethal target. Synthetic lethality is defined by an interdependent relationship between two genes, which means that simultaneous loss of two genes, but not loss of either gene alone, leads to cell death. Cancer cells harboring a LOF gene mutation would therefore be vulnerable to inhibition of the synthetic lethal target, as epitomized by the success of PARP1-targeted therapy against hereditary breast and ovarian cancers harboring LOF mutations of the BRCA1 and BRCA2 genes. Precision medicine based on synthetic lethality is promising for cancers with a LOF mutation gene. “Synthetic lethal therapy” is defined as cancer therapy based on synthetic lethality. This strategy is based on the assumption that a cancer patient has a LOF mutation of “Gene A” and Gene A is synthetic lethal with Gene B. In cancer cells, Gene A is the LOF gene, and therapy with an inhibitor of B causes cell death based on synthetic lethality because of the simultaneous suppression of the function of both A and B. In normal cells, Gene A is normal; therefore, inhibition of gene B does not affect the survival of normal cells. Synthetic lethal therapy is expected to have high selectivity against cancer cells and few side effects. Thus, the identification of cancer vulnerabilities associated with LOF gene mutations should lead to marked improvements in cancer therapy.
  Chromatin regulating factors are largely divided into two groups: chromatin remodeling complexes and histone modifying factors. Chromatin remodeling complexes use the energy of ATP hydrolysis and maintain chromatin structure by opening or closing chromatin through sliding, ejecting, repositioning, or inserting nucleosomes, which are histone octamers composed of histones H2A, H2B, H3, and H4. Histone modifying factors maintain the interaction between DNA and histones through histone methylation/demethylation, acetylation/deacetylation, and ubiquitylation/deubiquitylation. These chromatin regulating factors control binding of various functional proteins, such as transcription factors, DNA replication factors, DNA repair factors, and chromosome segregation factors to chromatin by remodeling and modifying chromatin structure. Therefore, chromatin regulating factors contribute to the regulation of transcription, DNA repair, DNA replication, and chromosomal segregation.
  Recent advances in genome wide sequencing technologies have contributed to the identification of most gene mutations associated with cancer. Comprehensive genome studies identified mutations in genes involved in chromatin regulation in approximately 50% of cancers. Most of the mutations in chromatin regulating genes are LOF mutations such as deleterious missense mutations, frameshift mutations, and chromosomal deletions.
  In this laboratory, we focus on chromatin regulator-deficient cancers. We aim to identify synthetic lethal targets for chromatin regulator-deficient cancers and elucidate mechanism of synthetic lethal relationship. We would like to develop therapeutic methods based on proof of concept of synthetic lethality.