# Predicting sensitivity and resistance in RET-driven cancers

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2022 · $396,790

## Abstract

Selpercatinib (LOXO-292) is a highly active selective RET inhibitor explored on an ongoing registrational
program (LIBRETTO-001 phase 1/2 trial) in RET-dependent cancers (US FDA approval in 2020 for RET
fusion-positive lung/thyroid cancer and RET-mutant thyroid cancer). Unfortunately, resistance is
uncharacterized and remains a liability. This proposal anticipates and addresses this unmet need by identifying
and functionally characterizing mechanisms of intrinsic and acquired genomic and non-genomic resistance to
selective RET inhibition in RET-dependent cancers. To accomplish this, we will leverage unique clinical,
computational, and translational resources at our disposal. Aim 1 will identify determinants of intrinsic
resistance to RET inhibition in RET-dependent cancers. Pre-treatment biopsies of selpercatinib responders
and non-responders will undergo targeted/whole exome sequencing. Computational analysis will explore the
role of clonality, allelic imbalance, and co-mutational signatures relative to selpercatinib response and
progression-free survival. Aim 2 will establish the mechanisms of acquired resistance to selective RET
inhibition. Paired pre-treatment and post-progression tumor biopsies and longitudinal cell-free (cf)DNA
(baseline, on-treatment, at/post- progression) from LIBRETTO-001 patients will be profiled. Utilizing paired
samples will allow for the identification of emergent genomic and non-genomic (including histologic/EMT
transformation) resistance mechanisms. In addition, plasma profiling will allow for a dynamic assessment of
selpercatinib resistance that captures the consequences of serial genomic evolution. Aim 3 will functionally
characterize resistance to selective RET inhibition. A unique and rich library of patient-derived models of
treatment-naïve and RET inhibitor resistant RET-dependent cancers will be augmented by ongoing prospective
collection and model development from LIBRETTO-001 and commercial use. In these models, on-target
(secondary RET mutations) and off-target (MET/PI3K/KRAS/MDM2 activation) resistance mechanisms will be
functionally characterized in terms of cell/tumor viability, receptor tyrosine kinase activation, and downstream
signaling dependencies. Novel therapeutic strategies, specifically RET tyrosine kinase inhibitor type switching
(on-target resistance) and combinatorial therapies (off-target resistance), will be explored in vitro and in vivo.
Optimal combination therapies will then be employed in compassionate use programs to confirm their
effectiveness and provide tailored, life-saving treatment to patients. In addition, patients with on-target
resistance will be treated on-protocol (Drilon PI) with the next-generation RET inhibitor, TPX-0046. This
proposal has both immediate and long-term relevance considering that about 400 patients have been treated
with selpercatinib around the world on trial and the potential approval and rapid adoption of this drug by
multiple regulatory agencies. Thes...

## Key facts

- **NIH application ID:** 10376881
- **Project number:** 5R01CA251591-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Alexander Drilon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $396,790
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10376881

## Citation

> US National Institutes of Health, RePORTER application 10376881, Predicting sensitivity and resistance in RET-driven cancers (5R01CA251591-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10376881. Licensed CC0.

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