Treatment resistance in diffuse large B-cell lymphoma: where, what and how

Where does it come from? What is the molecular basis? How can we manage it? These are the three key questions in terms of treatment resistance in diffuse large B-cell lymphoma. Herein, we comprehensively describe the sources, the molecular mechanisms and the ways to manage treatment resistance.

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Treatment resistance has been persistently a major challenge in the management of patients with diffuse large B-cell lymphoma (DLBCL), the most common subtype of lymphoma. It is highly aggressive and up to 40% of DLBCL patients will experience treatment failure upon the standard immunochemotherapy, which could lead to very poor survival outcomes. Although many novel therapies have recently emerged and some (e.g. CAR T-cell therapy) have shown great promise, treatment resistance seems to be inevitable in a subgroup of patients. So the key questions are: (1) where does treatment resistance originate from; (2) what is the molecular basis underlying treatment resistance; and (3) how can we rationally manage treatment resistance, in DLBCL. In searching for the answers to these questions, we found that there was a knowledge gap regarding comprehensive understanding of this topic in the literature. Hence, we were motivated to write a review in Leukemia to elaborate on these three “where, what and how” questions.

Where does treatment resistance originate from? DLBCL has a highly heterogeneous nature and it, essentially, can be regarded as a collection of multiple diseases with various mutational and non-mutational alterations. Beyond differences between tumors from individual patients, intrapatient heterogeneity has been clearly established. It is therefore not difficult to imagine that some cancer cells are intrinsically refractory and others may become resistant during the course of treatment. The interactions between cancer cells and their immediate surroundings, i.e., the tumor microenvironment additionally create a pro-tumor condition that nourishes the development of resistance by e.g., providing avenues to evade immune surveillance and offer protection from apoptosis. An often less considered but important factor — patient variabilities in terms of, for example, sex, age, body weight, polymorphisms and pharmacokinetic profile — also plays a critical role in treatment resistance.

What is the molecular basis underlying treatment resistance? The current standard treatment option for all patients with DLBCL is the immunochemotherapy R-CHOP while novel agents including epigenetic therapy, targeted therapy and immunotherapy have been evaluated in clinical trials. Multiple mechanisms of resistance to those therapeutic approaches have been revealed in recent preclinical and clinical studies, including alterations in signaling pathway activation, alternative signaling compensation, point mutation in drug targets, microRNA dysregulation, changes in metabolic profile, etc.

How can we rationally manage treatment resistance? Understanding treatment resistance is important to enable rational management of DLBCL patients. On one hand, successful prediction and dynamic monitoring for treatment resistance are always of great value in terms of preventing resistance. Examples include predictive biomarkers and liquid biopsy such as circulating tumor DNA-based technology for efficient patient stratification and early detection of potential resistance, respectively. Novel risk models are also highly useful in preventing the occurrence of resistance and quantitatively profiling personalized patient outcomes. On the other hand, many approaches have been investigated to overcome treatment resistance. For example, combination therapy provides the opportunity to simultaneously target multiple molecular vulnerabilities. Novel methods of targeting the epigenome and re-shaping the tumor microenvironment have further shown sensitizing effects to kill cancer cells.

We hope that our review could provide useful insight into treatment resistance in DLBCL to a broad readership and intrigue further investigation to enhance our understanding of this important issue towards better patient management. We encourage readers to find more details in our full-text publication

Preparation of the poster image was aided with BioRender.com.

Michael He

Postdoctoral Fellow, Princess Margaret Cancer Centre, University Health Network

Michael is studying treatment resistance and defining molecular vulnerabilities in B-cell lymphoma using cutting-edge functional genomics and other multi-omics technologies. His ultimate goal is to identify and validate therapeutic strategies and biomarkers to rationalize the clinical use of novel agents in treating B-cell lymphoma.