Targeting Drug Tolerant States + DNA Damage to Block Osimertinib Resistance

2021

EGFR Resisters / LUNGevity Research Award

Christine Lovly, MD, PhD

Vanderbilt University Medical Center

Nashville

Despite high tumor response rates, patients treated with EGFR targeted therapies, such as osimertinib, inevitably develop disease progression. Mechanisms of drug resistance remain incompletely understood on both a genomic and proteomic level. The objective of Dr. Lovly’s project is to find new targeted treatments and drug combinations that can tackle cancer evolution and osimertinib resistance.

Research Summary

The problem of EGFR TKI resistance has not been solved. Despite the impressive anti-tumor results observed for some lung cancer patients treated with immune checkpoint inhibitors targeting PD-1/PD-L1, these benefits do not seem to extend to patients whose tumors harbor EGFR mutations. As a result, there is an urgent need to optimize and extend the benefit of TKI therapy.

With osimertinib’s utilization in the first-line setting, there are now no FDA-approved targeted therapy options for patients who develop osimertinib resistance. The majority of studies to date have focused on treating osimertinib resistance once the resistance has already developed and the patient has signs of tumor growth. However, our focus is centered upon the development of up-front combination regimens that will block resistance before it emerges, analogous to the use of combination anti-microbials therapies for treatment of patients with TB and HIV.

We focus on analysis of drug-tolerant persistor cells (DTPCs) – the tumor that we can still see on scans in the clinic, even after patients have had a partial response to osimertinib. We seek to take partial shrinkage to complete tumor regression using cutting edge single cell biology techniques. We have assembled a team of expert investigators working collaboratively to tackle this pressing issue and develop new treatments for our patients in a complete bench to bedside manner. We also aim to train the next generation of researchers so that there is a robust and diverse pipeline in place to continue to advance lung cancer studies.

Technical Abstract

Despite high tumor response rates, patients treated with osimertinib inevitably develop disease progression. Mechanisms of both intrinsic, adaptive, and acquired drug resistance remain incompletely understood on a genomic and proteomic level. Our overall objective is to find new targeted treatments and drug combinations that can tackle cancer evolution and drug resistance.

We seek to:

Understand biological determinants of response prior to therapy (poor prognosis features)
Utilize correct combination therapies in the first line to enhance response, based on biological features of subpopulations present at the start
Reprogram cells toward a more drug-sensitive state through understanding network plasticity.

More specifically, our aims are:

To define the genomic and proteomic characteristics of drug-tolerant persister cells (DTPCs) under dynamic treatment with osimertinib. Our goal is to identify new vulnerabilities in EGFR-mutant tumors which, when therapeutically targeted, can maximize the depth and duration of benefit to first-line osimertinib therapy.
To decipher mechanisms of altered cell cycle progression and osimertinib-induced DNA damage that drive tumor progression.

We have assembled a collaborative, multi-disciplinary team of laboratory scientists and clinical investigators combined with cutting edge technologies to assess genetic and proteomic heterogeneity at the single cell level, access to a robust pipeline of patient samples, and strong preliminary data to support our studies. The proposed aims are expected to define the molecular determinants of tumor heterogeneity and to develop rational therapeutic strategies for delaying / overcoming resistance. These synergistic aims are highly relevant to the current landscape of EGFR-mutant lung cancer.

Key words

Acquired resistance

Adenocarcinoma

Biomarker or biomarker testing

Epidermal growth factor receptor (EGFR)

Metastatic

Molecular profile or molecular testing

Mutation profile

Non-small cell lung cancer (NSCLC)

Small cell lung cancer (SCLC)

Squamous cell lung cancer

Stage III