MOLECULAR MECHANISMS OF RITUXIMAB RESISTANCE AND STRATEGIES TO OVERCOME THEM

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Abstract

Rituximab is the first anti-CD20 chimeric-monoclonal antibody utilized for patients, and is now a key molecular targeting drug for CD20-positive B-cell lymphomas (BCL). Although combination chemotherapies with rituximab have surely improved the clinical outcomes of BCL patients, many clinicians recognize that relapse/refractory disease, which occurs in almost 50% of BCL patients, is still a major problem. Confirming the molecular mechanisms of rituximab resistance is crucial for further improvement of overall survival and progression-free survival in BCL patients. Several mechanisms of rituximab resistance have recently been reported as follows: (i) downregulation of CD20 expression after using rituximab, (ii) low expression level of CD20 at diagnosis, (iii) CD20 genetic mutations, (iv) aberrant expression of complement regulatory molecules (e.g. CD55, CD59) on tumor cells), (v) disruption of lipid raft formation, (vi) abnormality of signal transduction pathway, and (vii) Fc-gamma receptor polymorphisms of effector cells. To overcome these phenomena, several strategies are considered: (i) utilization of newer generation anti-CD20 antibodies (e.g. type I and II antibodies), (ii) new monoclonal antibodies for other targets (e.g. anti-CD22, -CD23, -CD79), and (iii) combination therapy with other molecular targeting drugs (e.g. demethylating and deacetylating agents, BH3 mimetics). In this session, recent progress in molecular analyses of resistant mechanisms and the strategies to overcome them will be summarized. Understanding these mechanisms may provide quite important information for not only improving clinical outcomes of BCL patients but also confirming the resistance mechanisms against newer monoclonal antibodies for BCL and solid tumors.

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