EGFR Resisters
Susumu Kobayashi, MD, PhD
Beth Israel Deaconess Medical Center
Boston
Tyrosine kinase inhibitors (TKI) are a class of drugs that are used to treat EGFR NSCLC. These drugs eventually stop working and some cancer cells called drug-tolerant persisters (DTPs) are implicated in this resistance. Dr. Kobayashi and his team have found that a protein called CD74 plays a role in developing a resistance to osimertinib. In this project, he will investigate whether CD74-expressing cells allow for the development of DTPs and if inhibition of CD74 by combining an antibody-drug conjugate (CD74-MMAE) with osimertinib, prevents resistance. If successful, this has the potential to significantly impact the survival of EGFR patients by allowing them to stay on osimertinib for a longer duration.
Research Summary
Non-small cell lung cancer (NSCLC) with certain mutations in the EGFR gene at advanced stages can be treated with drugs called EGFR tyrosine kinase inhibitors (TKIs). However, these drugs can eventually stop working as cancer cells develop resistance. Recent evidence suggests that some cancer cells called drug-tolerant persisters (DTPs) are responsible for this resistance. These cells survive and adapt to TKIs during early phases of therapy, and can give rise to resistant cells through various mechanisms. Therefore, targeting DTPs may be a way to prevent resistance to EGFR TKIs. Our research team has found that a protein called CD74 plays a critical role in the drug-tolerant state of cancer cells. We have found that CD74 upregulation signals resistance to a third-generation EGFR TKI called osimertinib, and blocks apoptosis, which allows tumors to grow back. Based on these findings, we hypothesize that elimination of CD74-expressing cells in addition to EGFR inhibition may be a better treatment strategy than EGFR inhibition alone, because it could suppress the emergence of DTPs. In our proposed research, we will investigate whether CD74-expressing cells give rise to DTPs, and how CD74 is upregulated and prevents apoptosis in tumor cells exposed to osimertinib. We will also evaluate the effectiveness of CD74-antibody-drug conjugates (ADCs) alone or in combination with EGFR TKIs using cell culture systems and animal models. CD74-ADCs target and eliminate tumor cells expressing CD74 on the cell surface. Our goal is to better understand the mechanisms underlying resistance to EGFR-TKIs and the emergence of DTPs, and provide preclinical evidence that combined inhibition of CD74 and EGFR is a rational and effective treatment strategy for EGFR-mutated lung cancer.
Technical Abstract
The development of tyrosine kinase inhibitors (TKIs) revolutionized treatment of advanced/metastatic non-small-cell lung cancer with EGFR mutations. Osimertinib is one of several third-generation EGFR TKIs and shows improvement in progression-free survival and overall survival compared to first- and second-generation EGFR TKIs. However, intrinsic or acquired resistance to osimertinib emerges in essentially all patients, which prevents a cure for EGFR-mutated lung cancer. Therefore, it is necessary to develop better strategies to improve clinical outcomes. Recent evidence suggests that drug-tolerant persister (DTP) populations of cancer cells, which survive and adapt to TKIs during early phases of therapy, play an important role in the emergence of resistance to targeted therapies. Such DTP cells give rise to resistant cells via diverse mechanisms and contribute to spatial and temporal heterogeneity of tumors. Therefore, targeting DTP cells may be an efficient strategy to prevent resistance to EGFR TKIs. Using lung cancer cell line models and clinical specimens, we recently identified CD74 as a novel gene that plays a critical role in the drug-tolerant state. In vitro and in vivo experiments demonstrate that CD74 upregulation signals osimertinib resistance and blocks apoptosis, enabling tumor regrowth. Based on preliminary evidence, we hypothesize that CD74 increases tumor cell survival in the presence of TKIs and that elimination of CD74 positive cells by CD74-antibody-drug conjugates (ADCs) may suppress the emergence of DTP cells, which underlie relapse. In this proposal, we will test this hypothesis by: 1) confirming that CD74-positive cells are tolerant to EGFR TKIs; 2) investigating the mechanisms by which osimertinib induces CD74 expression; and 3) evaluating a combination of CD74-ADCs and osimertinib to prevent the emergence of acquired resistance. We will address these questions using cell culture systems and animal models. These experiments should unveil the mechanisms underlying resistance to EGFR-TKIs and the emergence of DTP cells, and provide preclinical evidence that a combination of CD74-ADC and EGFR TKIs is a rational and efficacious treatment strategy for EGFR-mutated lung cancer.