# Targeting bidirectional signaling in lung stroma and cancer cells

> **NIH NIH R01** · H. LEE MOFFITT CANCER CTR & RES INST · 2020 · $506,795

## Abstract

PROJECT ABSTRACT
Resistance to tyrosine kinase inhibitors (TKI) in lung cancer (LC) is often connected to cancer-associated
fibroblasts (CAFs), a major component of the tumor microenvironment (TME). CAFs can cause drug resistance via
secretion of growth factors as well as direct contact with cancer cells. Furthermore, tumor cells educate TME
fibroblasts to adapt a CAF phenotype, leading to complex and bi-directional signaling between cancer cells and
CAFs. Importantly, TKIs do not simply shut down oncogenic signaling, but lead to an adaptive rewiring of the
signaling network. In addition, most TKIs have multiple targets, and TKI off-targets can have important effects
on efficacy and response, either by restricting or boosting it. This is not limited to cancer cells, but TKIs can
simultaneously engage proteins and signaling pathways in cancer as well as stromal cells. Together, these
scenarios create a highly dynamic, bi-directional and drug-specific adaptive signaling response of the cancer
cell/CAF system, which results in modulation of drug sensitivity and development of drug-tolerant “persister”
cell populations. We hypothesize a) that individual TKIs elicit drug- and cell-specific adaptive signaling
responses and resistance mechanisms in the LC cell/CAF system, and b) that disrupting bi-directional
signaling between LC cells and CAFs can enhance drug sensitivity and eliminate CAF-supported persister
cells. Using unbiased, cell type-specific proteomics approaches, we will test these hypotheses in the following
specific aims: 1) To characterize mechanisms and roles of fibroblast RTK pathway activation by cancer cells.
Genetically activating RTK-driven signaling pathways inside CAFs will allow the characterization of bi-directional
signaling of CAFs and LC cells using “cell type-specific labeling using amino acid precursors” (CTAP)-based
phosphoproteomics and how it in turn affects LC cell proliferation, invasion and drug sensitivity. Relevant
signaling pathways will be evaluated by proximity-ligation assays on patient-derived tissue microarrays (TMAs)
and in orthotopic, heterotypic in vivo models. 2) To develop strategies to functionally engage TKI-induced
adaptive signaling in CAFs and LC cells. Using CTAP-based chemical and phosphoproteomics, we will
determine LC- and CAF-specific adaptive signaling responses and target profiles of clinical TKIs. Functional
validation by RNAi and rescue experiments will identify CAF targeting drugs. Synergy with TKI will be
evaluated in co-culture and in patient-derived xenograft (PDX) models. The approach is innovative, because it
represents a novel way of targeting cancer by developing strategies to simultaneously engage signaling pathways
in cancer cells as well as the TME, which are enabled by application of state-of-the-art proteomics. The proposed
research is significant as it will transform our understanding of the dynamics and complexity of signaling
evoked by LC cell-CAF interactions and the roles of...

## Key facts

- **NIH application ID:** 9982983
- **Project number:** 5R01CA219347-04
- **Recipient organization:** H. LEE MOFFITT CANCER CTR & RES INST
- **Principal Investigator:** ERIC B. HAURA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $506,795
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982983

## Citation

> US National Institutes of Health, RePORTER application 9982983, Targeting bidirectional signaling in lung stroma and cancer cells (5R01CA219347-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9982983. Licensed CC0.

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