# Uncovering the Biology of Resistance to Tyrosine Kinase Inhibitors in EGFR Mutant Lung Cancer Patient-Derived Models.

> **NIH NIH U01** · YALE UNIVERSITY · 2020 · $798,050

## Abstract

PROJECT SUMMARY
 A long-standing clinical observation is that metastatic cancers are refractory to treatment. Even with the advent
of molecularly targeted therapies, drug resistance almost always emerges and patients ultimately succumb to
further metastatic spread of the cancer. In the case of EGFR mutant lung adenocarcinoma (LUAD), tumors can
acquire resistance to tyrosine kinase inhibitors (TKI) while spreading to the liver and brain. The mechanisms
linking these morbid outcomes remain poorly understood. Here, we propose to study the biological properties of
EGFR mutant tumors as they evolve through TKI treatment, identify the factors that allow treated tumor cells to
persist and how features of the metastatic niche and depth (or durability) of responses to TKIs are linked. We
hypothesize that, 1) the tumor microenvironment (TME) and tumor cell extrinsic factors are critical determinants
of disseminated tumor cell persistence following TKI treatment and 2) that the reliance on these factors decreases
in highly resistant metastasis through sequential TKI treatment.
 To study this hypothesis, we have successfully established a repeat biopsy program to collect and analyze
lung cancer specimens, including EGFR mutant LUADs before and after TKI treatment. Through this program we
have established >20 patient-derived models of EGFR mutant LUAD, including organoid cultures and
subcutaneous and orthotopic patient-derived xenografts (PDXs). In Aim 1, we will generate additional patient-
derived models of cancer (PDMCs) as organoids, subcutaneous or orthotopic PDXs, collected from 10 patients
with EGFR mutant LUAD longitudinally prior to TKI treatment and at acquired resistance to TKIs. These PDMCs
will be genomically and histologically characterized, while their TKI sensitivity will be compared to the patient
specimens. In Aim 2, we will leverage these models to determine the mechanisms by which TKI resistance affects
the aggressiveness of EGFR mutant tumors. Using paired pre- and post-TKI PDMCs, we will evaluate the latency
and site of relapse of these tumors. We will also determine how known mechanisms of TKI resistance affect the
metastatic properties of EGFR mutant tumors and identify novel dual molecular mediators of resistance and
metastasis. Finally, in Aim3, we will Identify tissue-specific determinants of tumor cell persistence following TKI
treatment. Focusing on tumors that we know are responsive to specific TKIs, we will establish whether tumors
implanted in different sites of metastases exhibit different sensitivity to TKIs and identify the cellular, molecular
and pharmacological determinants of these differences. We will test the mechanistic prediction that the stromal
extracellular matrix modulates the ability of tumor cells to persist upon TKI treatment.
 Thoracic malignancies account for most cancer-related deaths. By integrating the complementary expertise
and resources of 2 principal investigators and collaborators, our aims will provi...

## Key facts

- **NIH application ID:** 9920134
- **Project number:** 5U01CA235747-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Don X Nguyen
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $798,050
- **Award type:** 5
- **Project period:** 2019-04-23 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9920134

## Citation

> US National Institutes of Health, RePORTER application 9920134, Uncovering the Biology of Resistance to Tyrosine Kinase Inhibitors in EGFR Mutant Lung Cancer Patient-Derived Models. (5U01CA235747-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9920134. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*