# Regulation of lung cancer growth and metastasis by an actionable driver of vesicle biogenesis in the Golgi

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $421,158

## Abstract

Few effective therapies are available for KRAS-mutant lung cancer
(KMLC). To address this problem, we seek to elucidate the biological basis for KMLC growth and metastasis
and to develop novel therapies on the basis of that improved understanding. Cancer cells secrete factors that
promote tumor growth, matrix remodeling, angiogenesis, and inflammation, a process hereafter termed
“malignant secretion”. Therapeutic strategies to block malignant secretion have not been developed.
 We have identified a chromosome 1q amplicon harboring and numerous regulators of vesicle biogenesis
and trafficking, including phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ), a Golgi-dedicated kinase that generates
phosphatidylinositol 4-phosphate (PI4P). We show that the viability and proliferative and invasive activities of
1q–amplified KMLC cells require PI4KIIIβ. A selective PI4KIIIβ antagonist preferentially induced apoptosis and
inhibited the metastatic properties of 1q–amplified KMLC cells. On the basis of these findings, we hypothesize
that high PI4KIIIβ levels promote KMLC growth and metastasis and confer vulnerability to PI4KIIIβ antagonists.
To test this hypothesis, we propose in Aim 1 to an autochthonous PI4KIIIβ–expressing KMLC model and
determine whether PI4KIIIβ enhances KMLC metastatic propensity and confers vulnerability to PI4KIIIβ
antagonists. Our findings will elucidate the way in which PI4KIIIβ drives KMLC progression and may provide a
foundation for new therapeutic approaches using PI4KIIIβ antagonists.
 We show that high PI4KIIIβ levels in 1q–amplified KMLC cells enhanced anterograde vesicular trafficking
and stimulated the secretion of pro-survival and pro-metastatic factors. PI4KIIIβ–driven metastatic properties
required Golgi phosphoprotein 3 (GOLPH3), a PI4P–tethered Golgi protein that promotes vesicle budding from
the trans-Golgi network. Therefore, we postulate that PI4KIIIβ-dependent secretion is required to activate pro-
metastatic processes in the tumor microenvironment and maintain the viability of 1q-amplified KMLC cells. To
test this hypothesis, we will inactivate Golph3 in PI4KIIIβ-expressing autochthonous KMLCs and 1q-amplified
orthotopic KMLCs. Resultant changes in tumor cell viability and inflammatory, stromal, and vascular cell
functions in the tumor microenvironment will be measured. We will identify PI4KIIIβ-dependent secreted
proteins that mediate these changes and elucidate how they exert these functions. Our findings will provide
insight into how a secretory process activated by a chromosomal region that is frequently amplified in cancer
maintains tumor cell viability and influences diverse processes in the tumor microenvironment.
 In summary, the evidence presented here links malignant secretion to a chromosomal region that is
frequently amplified in KMLC and provides a basis for clinical studies to develop PI4KIIIβ antagonists as first-
in-class inhibitors of malignant secretion. Our findings elucidate the molecular underpinnin...

## Key facts

- **NIH application ID:** 10739321
- **Project number:** 5R01CA236781-05
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Jonathan M Kurie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $421,158
- **Award type:** 5
- **Project period:** 2019-12-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10739321

## Citation

> US National Institutes of Health, RePORTER application 10739321, Regulation of lung cancer growth and metastasis by an actionable driver of vesicle biogenesis in the Golgi (5R01CA236781-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10739321. Licensed CC0.

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