# Defining the role of macropinocytosis in solid tumor growth and therapeutic resistance

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2021 · $349,523

## Abstract

ABSTRACT
Cancer cells require a steady stream of nutrients to support their oncogene-driven growth. However, the blood
vessels that supply these nutrients are often tortuous and leaky. Desmoplasia can also lead to elevated
interstitial pressure that collapses tumor blood vessels, further compromising nutrient delivery. Cancer cells
overcome these supply-side limitations by scavenging macromolecules from the microenvironment. One
scavenging strategy employed by tumors is macropinocytosis, a process by which extracellular material is non-
specifically engulfed and then degraded in the lysosome to produce nutrients. Oncogenic mutations in RAS,
activation of the PI3K pathway, and EGFR and WNT signaling drive macropinocytosis in pancreatic, prostate,
lung, colon, bladder, and breast cancer cell lines. When provided with macropinocytic fuel, these cancer cells
are able to proliferate in nutrient-limiting conditions. However, is not currently clear whether the quantity and
quality of material present in the tumor microenvironment is sufficient for macropinocytosis to make a
significant contribution to tumor anabolism. All published studies have depended upon EIPA for in vivo
macropinocytosis inhibition. EIPA is an inhibitor of Na+/H+ exchangers that has pleiotropic anti-neoplastic
effects independent of macropinocytosis inhibition. What is currently lacking is a strategy to selectively disrupt
macropinocytosis in vivo. As a result, it has not been possible to accurately define the contribution of
macropinocytosis to tumor growth or the potential therapeutic value of targeting this pathway. Given that
nutrient recycling via autophagy plays a major role in both tumor progression and therapeutic resistance, it is
likely that nutrient scavenging through macropinocytosis will play a similarly important role. Aim 1 of this
proposal will assess the extent to which selective macropinocytosis inhibition limits tumor growth. Aim 2 will
evaluate the role of macropinocytosis in therapeutic resistance. Aim 3 will dissect the signals that promote
macropinosome formation in tumor cells. Completing these studies will fill major gaps in our knowledge and
could lead to new single-agent and/or combination therapies for cancer. Because some of the most difficult to
treat cancers are macropinocytic (e.g. pancreas, KRAS+ colorectal, triple-negative breast, and castration-
resistant prostate cancers), these studies have the potential to make a significant impact on patient survival.

## Key facts

- **NIH application ID:** 10115004
- **Project number:** 5R01CA247556-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Aimee L Edinger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $349,523
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10115004

## Citation

> US National Institutes of Health, RePORTER application 10115004, Defining the role of macropinocytosis in solid tumor growth and therapeutic resistance (5R01CA247556-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10115004. Licensed CC0.

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