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Modulation of Therapeutic Response in Lung Cancer by Tumor Suppressor LKB1

Award Number: R01CA304148
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Modulation of Therapeutic Response in Lung Cancer by Tumor Suppressor LKB1 - Project Summary/Abstract: Non–small cell lung cancer (NSCLC) frequently harbors inactivating mutations in the tumor suppressor gene LKB1 (STK11), which are associated with aggressive growth, metastatic progression, and resistance to standard therapies, including immune checkpoint blockade. However, the mechanisms by which LKB1 deficiency drives immune evasion and therapeutic resistance remain poorly understood. Understanding how LKB1 inactivation alters cancer cell–immune interactions could reveal new therapeutic opportunities. Our recent singlecell RNA sequencing studies reveal that LKB1 loss suppresses CIITA, the master regulator of MHC class II, leading to reduced expression of MHC II pathway genes in tumor cells. This defect likely impairs early immune recognition essential for effective antitumor responses. Using syngeneic tumor models, human NSCLC cell lines, and patient datasets, we validated the link between LKB1 deficiency and diminished MHC II pathway activity, implicating impaired tumor-intrinsic MHC II presentation as a driver of immune evasion and treatment resistance. We hypothesize that LKB1 inactivation represses CIITA and MHC II expression in cancer cells, impairing antigen presentation and promoting immune evasion. Restoring CIITA/MHC II may reverse immune suppression, enhance antitumor immunity, and improve responsiveness to immunotherapy. Our research will pursue two specific aims: Aim 1 will define the regulation and role of tumor cell-intrinsic CIITA/MHC II in LKB1-deficient lung cancer. Aim 2 will evaluate the impact of restoring CIITA/MHCII levels in LKB1-mutant lung cancer on enhancing antitumor immunity and improving treatment responses. This project addresses a critical gap by defining how LKB1 inactivation drives immune evasion and therapy resistance. It will establish a new mechanistic framework and therapeutic strategy to target cancer cell–intrinsic antigen presentation in LKB1-mutant NSCLC, a common, aggressive, and treatment-refractory subtype. This project involves the use of vertebrate animals because mouse models are necessary to study tumor development, tumor-immune interactions, and immunotherapy responses in a physiologically relevant system that cannot be replicated in vitro or in lower species. The selected genetically engineered, syngeneic, immunodeficient, and humanized models are well-validated and essential for achieving the study’s objectives, including modeling native tumor environments and immune responses.


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 = $487,056 )
2026	2026	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cancer Biology Research	000	1	6/19/2026	NEW	$487,056
														Subtotal = $487,056

Grand Total All Awards = $487,056

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Modulation of Therapeutic Response in Lung Cancer by Tumor Suppressor LKB1

Award Number: R01CA304148

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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