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Targeting mucin-type O-glycosylation for EGFR mutant non-small cell lung cancer

Award Number: R01CA300241
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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Targeting mucin-type O-glycosylation for EGFR mutant non-small cell lung cancer - PROJECT SUMMARY Lung cancer is the leading cause of cancer-related deaths among both men and women in the United States with non-small cell lung cancer (NSCLC) accounting for 85% of all lung cancers. Epidermal growth factor receptor (EGFR) activating mutation is one of the most common actionable oncogenic driver mutations in NSCLC, found in around 30% of NSCLC patients. The subsequent development of targeted therapy with small-molecule EGFR tyrosine kinase inhibitors (TKIs) has dramatically revolutionized the treatment landscape of these tumors. Several large-scale Phase 3 clinical trials have consistently demonstrated the superior efficacy of EGFR inhibitors (particularly osimertinib) in comparison with standard platinum-based chemotherapy for NSCLC patients with activating EGFR mutations. Unfortunately, despite a remarkably high (60–70%) objective response rate (ORR) to such treatments, patients inevitably develop resistance, leading to treatment failure. Therefore, better understanding the oncogenic EGFR signaling in NSCLC could lead to novel combination therapy approaches and improve patient survival. O-linked glycosylation is a widespread post-translational modification found on membrane and secreted proteins. The most prevalent form of O-linked glycosylation, known as the mucin type, is characterized by an N- acetylgalactosamine (GalNAc) residue α-linked to the hydroxyl group of serine or threonine, which is initiated by a family of ~20 polypeptide N-acetyl--galactosaminyltransferases (GALNTs). It has been widely reported that extensive aberrant mucin-type O-glycosylation mediated by GALNTs occur in various cancer types, but the impact of such deregulated O-glycosylation on the function of cell surface proteins such as receptor tyrosine kinase is largely unexplored. As part of our larger effort to identify novel regulators of oncogenic EGFR signaling in NSCLC, we discovered that mucin type O-linked glycosylation, through N-acetyl--galactosaminyltransferase 3 (GALNT3 or GalNAc T3), plays an important role in sustaining survival signal in EGFR mutant NSCLC. Mechanistically, GALNT3 initiates O-linked glycosylation of HER3, leading to stabilization of HER3 protein and sustaining of HER3-PI3K-AKT signaling, which further promotes cell survival. Thus, pharmacological targeting GALNT3 reduces HER3-PI3K mediated survival signaling and improves the efficacy of clinical EGFR inhibitors such as osimertinib in EGFR mutant NSCLC. We will test our hypothesis through the following aims: Specific Aim 1: To investigate how GALNT3 regulates HER3-AKT signaling in EGFR mutant non-small cell lung cancer. Specific Aim 2: To elucidate how osimertinib suppresses GALNT3-mediated O-glycosylation. Specific Aim 3: To validate GALNT3 as a novel therapeutic target for improving anti-EGFR therapy in EGFR mutant NSCLC.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $609,846 )
2026	2026	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Treatment Research	000	1	3/27/2026	NEW	$609,846
														Subtotal = $609,846

Grand Total All Awards = $609,846

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Targeting mucin-type O-glycosylation for EGFR mutant non-small cell lung cancer

Award Number: R01CA300241

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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