Identifying non-genomic mechanisms of RET TKI resistance

2022

Grant title (if any)

Hamoui Foundation / LUNGevity Lung Cancer Research Award

Alexander Drilon, MD

Memorial Sloan Kettering Cancer Center

New York

Many RET-positive cancers become resistant to targeted therapy for reasons not clearly based on genetic changes alone. Dr. Drilon predicts that other causes of resistance include (1) chemical changes (in the “epigenome”) that turn cancer-causing genes on or off and (2) changes in how these cancers look under the microscope (“histology”) that affect cancer behavior. Because these changes affect cell states rather than mutations, this resistance is potentially reversible, defining a key opportunity to maintain, restore, and extend sensitivity to potent and specific RET inhibitors.

Research Summary

Understanding how RET-positive lung cancers become resistant to targeted therapy is crucial. Most of what we know is limited to how these cancers develop secondary mutations (like changes in RET itself) that cause resistance. This knowledge is insufficient. Many RET-positive cancers become resistant to targeted therapy for reasons not clearly based on genetic changes alone. To develop new treatments, we need to know what causes resistance in these cancers. The goal of this project is to bridge this knowledge gap. We predict that other causes of resistance include (1) chemical changes (in the “epigenome”) that turn cancer genes on or off and (2) changes in how these cancers look under the microscope (“histology”) that affect cancer behavior. We hope to characterize these changes and expand our anticancer arsenal by developing new strategies to treat patients whose RET-positive lung cancers develop resistance in these ways. Because these changes affect cell states rather than mutations, this resistance is potentially reversible, defining a key opportunity to maintain, restore, and extend sensitivity to potent and specific RET inhibitors.

Technical Abstract

On-/off-target resistance mechanisms to RET tyrosine kinase inhibition (TKI) are not identified in ~40% of patients with RET fusion-positive lung cancers. As such, focusing solely on genomic alterations (e.g. mutation/amplification) limits our ability to develop novel therapies for all patients. This project addresses the unmet need of identifying and characterizing alternate resistance mechanisms to selective RET TKI therapy via epigenetic mechanisms leading to altered programs of gene expression. As with other oncogene-TKI pairs, we hypothesize that epigenetic re-programming and lineage plasticity drives resistance to RET TKIs. Serial pre- and post-TKI tumor samples will be interrogated (DEG/GSEA analysis) via complementary methylome (EPIC) and transcriptomic (RNAseq) profiling. Pathologic review and immunohistochemical profiling for markers of squamous (p40, CK5/6), small cell (chromogranin, synaptophysin), and epithelial-mesenchymal (E/N-cadherin, vimentin) transformation will be performed. Candidate resistance pathways will be explored in engineered isogenic overexpression/knockout models and our institutional library of xenografts generated from patients treated with a selective RET TKI on a registrational program or standard of care. Genetic manipulation of targets that we and others have associated with licensing lineage plasticity (e.g. myrAKT, MYC, EZH2, and beta-catenin) in RET fusion-positive models to induce histologic transformation will be performed. These analyses will define strategies to constrain or abrogate therapeutic resistance.

Identifying non-genomic mechanisms of RET TKI resistance

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