Targeting lineage plasticity to suppress DTP in RET-positive lung cancer

2022

Grant title (if any)

RETpositive / LUNGevity Foundation Lung Cancer Research Award

Hideo Watanabe, MD, PhD

Icahn School of Medicine at Mount Sinai

New York

Despite an initial response to the newly approved RET inhibiting drugs, most RET-positive lung cancers become resistant to these drugs and the cancers relapse. Dr. Watanabe’s project will provide anti-relapse therapeutic strategies for RET-positive lung cancer that target newly identified “drug-tolerant persisters (DTPs)”. DTPs are a small population of cancer cells that do not respond to these drugs and therefore start growing, leading to the relapse of these cancers. The role of DTPs in RET-positive lung cancer is not well understood. Dr. Watanabe proposes therapeutic strategies, such as targeting the Wnt and Hippo signaling pathway to overcome the DTP adaptability and prevent relapse before these cells arise.

Research Summary

Lung cancer remains the number one cause of cancer-related deaths despite recent advances in targeted therapeutics revolution. Hitherto, seven driver genes (EGFR, ALK, ROS1, BRAF, NTRK, MET and RET) have FDA-approved targeted therapies. However, those drugs largely fail to eradicate the disease due to acquired resistance. The development of resistance is a serious issue that demands investigating to improve long-term outcomes for patients. Some genetic and non-genetic mechanisms have been uncovered in the context of common mutations such as EGFR or KRAS, while knowledge for those rare mutations like RET are very limited. This study will provide a new perspective of anti-relapse therapeutic strategies for RET-positive lung cancer, that target a newly identified “drug-tolerant persisters (DTPs)” through chromatin (packaged DNAs) enzymes that dictate cell states and developmental pathways essential for DTP survival and adaptability to change their states later. HDAC inhibitors have been subjected to numerous clinical trials in lung cancers with overall inadequate outcome, partly due to imprecise clinical context. We will characterize the chromatin dynamics of Selpercatinib-induced DTP, and target chromatin enzymes in RET-positive lung cancer to prevent relapse building on our initial observation. DTP cells contains heterogeneous populations that potentially develop different paths to acquire resistance. We will determine the function of HOPX, a factor defining lung cell state for DTP survival and adaptability. We propose therapeutic strategies (Wnt and Hippo inhibitions) to overcome the DTP adaptability, an untested targetable vulnerability of DTPs and prevent relapse before heterogeneous resistance mechanisms to arise.

Technical Abstract

Genomic discoveries of driver-gene alterations in lung cancer have led to development of effective target therapeutics; however patients who initially respond to the therapy inevitably experience regrowth of the disease. The reversible drug-tolerant persister (DTP) stage, where cells enter a quiescence, is gaining attention as a major source of non-genetic drug resistance. In our EGFR-TKI-induced DTP model, we found a marked overload of repressive chromatin modification (H3K9me3 and H3K27me3) reminiscent of a quiescent state. In Aim1, we seek to characterize the epigenomic dynamics of DTP stage in RET-positive lung cancer under Selpercatinib treatment, and determine the roles of histone-modifying enzymes on maintaining DTP stage as potential combinatorial therapeutic targets. The process of DTP development requires terminally differentiated cells to regain plasticity and undergo re-differentiation, while the origin of DTP plasticity remains unknown. A recent scRNA-seq study from lung cancer biopsies representing DTP states showed an elevated alveolar signature. During lung regeneration, an alveolar lineage factor HOPX is required for the AT1 plasticity to regenerate AT2 cells upon injury, suggesting a differentiation potential of HOPX(+) cells. Our data showed HOPX is an early marker for treatment-induced DTP and necessary for DTP development, where our scATAC-seq data exhibited increased epigenomic heterogeneity. We hypothesize DTP contains heterogeneous subpopulations that hijack developmental pathways to sustain plasticity for subsequent differentiation. In Aim2, we will determine the role of HOPX and associated developmental pathways in RET-induced DTP model, to identify novel targets determining the DTP plasticity thereby preventing relapse from heterogeneous pathways to acquire Selpercatinib resistance.

Targeting lineage plasticity to suppress DTP in RET-positive lung cancer

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