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Culture of Bladder Cancer Organoids as Precision Medicine Tools
Published on: December 28, 2021
Microsatellite instability and immune checkpoint inhibitors: toward precision medicine against gastrointestinal and
Yuji Eso1, Takahiro Shimizu1, Haruhiko Takeda1
1Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto, 6068507, Japan.
Abstract:
Recent innovations in the next-generation sequencing technologies have unveiled that the accumulation of genetic alterations results in the transformation of normal cells into cancer cells. Accurate and timely repair of DNA is, therefore, essential for maintaining genetic stability. Among various DNA repair pathways, the mismatch repair (MMR) pathway plays a pivotal role. MMR deficiency leads to a molecular feature of microsatellite instability (MSI) and predisposes to cancer. Recent studies revealed that MSI-high (MSI-H) or mismatch repair-deficient (dMMR) tumors, regardless of their primary site, have a promising response to immune checkpoint inhibitors (ICIs), leading to the approval of the anti-programmed cell death protein 1 monoclonal antibody pembrolizumab for the treatment of advanced or recurrent MSI-H/dMMR solid tumors that continue to progress after conventional chemotherapies. This new indication marks a paradigm shift in the therapeutic strategy of cancers; however, when considering the optimum indication for ICIs and their safe and effective usage, it is important for clinicians to understand the genetic and immunologic features of each tumor. In this review, we describe the molecular basis of the MMR pathway, diagnostics of MSI status, and the clinical importance of MSI status and the tumor mutation burden in developing therapeutic strategies against gastrointestinal and hepatobiliary malignancies.
Insights
Mismatch repair deficiency (dMMR) causes microsatellite instability (MSI-H) in tumors. MSI-H/dMMR tumors show promising responses to immune checkpoint inhibitors, revolutionizing cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Genetic alterations drive cancer development.
- DNA repair pathways, particularly mismatch repair (MMR), are crucial for maintaining genomic stability.
- MMR deficiency results in microsatellite instability (MSI), a hallmark of cancer predisposition.
Purpose of the Study:
- To review the molecular basis of the MMR pathway.
- To discuss diagnostics for MSI status.
- To highlight the clinical significance of MSI status and tumor mutation burden in therapeutic strategies for gastrointestinal and hepatobiliary cancers.
Main Methods:
- Literature review of MMR pathway mechanisms.
- Analysis of MSI diagnostic methods.
- Synthesis of clinical data on MSI status and immune checkpoint inhibitor efficacy.
Main Results:
- MMR deficiency leads to MSI-H tumors.
- MSI-H/dMMR tumors exhibit significant response to immune checkpoint inhibitors (ICIs) like pembrolizumab.
- This response has led to new therapeutic indications for advanced or recurrent solid tumors.
Conclusions:
- Understanding MMR pathway and MSI status is critical for optimizing ICI therapy.
- MSI status and tumor mutation burden are key factors in developing personalized treatment strategies.
- This review provides insights into MMR, MSI diagnostics, and their therapeutic implications in GI and hepatobiliary malignancies.
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