TY - JOUR
T1 - STK11/LKB1 mutations in NSCLC are associated with KEAP1/NRF2-dependent radiotherapy resistance targetable by glutaminase inhibition
AU - Sitthideatphaiboon, Piyada
AU - Galan-Cobo, Ana
AU - Negrao, Marcelo V.
AU - Qu, Xiao
AU - Poteete, Alissa
AU - Zhang, Fahao
AU - Liu, Diane D.
AU - Lewis, Whitney E.
AU - Kemp, Haley N.
AU - Lewis, Jeff
AU - Rinsurongkawong, Waree
AU - Giri, Uma
AU - Lee, J. Jack
AU - Zhang, Jianjun
AU - Roth, Jack A.
AU - Swisher, Stephen
AU - Heymach, John V.
N1 - Funding Information:
This work was supported by The University of Texas Southwestern Medical Center and The University of Texas MD Anderson Cancer Center Lung UT; Lung SPORE P50CA07907; The LKB1 R01 CA205150; CPRIT CP160652; The Lung Cancer Moon Shot, including donations from Kyte Family, Jeff Hepper, and Normal Godinho; Rexanna's Foundation for Fighting Lung Cancer; Weaver Foundation; CCSG CA016672; a Stand Up to Cancer-American Cancer Society Lung Cancer Dream Team Translational Research Grant (SU2C-AACR-DT17-15), and a Jane Ford Petrin donation. Stand Up to Cancer is a division of the Entertainment Industry Foundation. The indicated SU2C grant is administered by the American Association for Cancer Research, the scientific partner of SU2C.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/3
Y1 - 2021/3
N2 - Purpose: Radiotherapy with or without chemotherapy is a mainstay of treatment for locally advanced non-small cell lung cancer (NSCLC), but no predictive markers are currently available to select patients who will benefit from these therapies. In this study, we investigated the association between alterations in STK11/LKB1, the second most common tumor suppressor in NSCLC, and response to radiotherapy as well as potential therapeutic approaches to improve outcomes. Experimental Design: We conducted a retrospective analysis of 194 patients with stage I-III NSCLC, including 164 stage III patients bearing mutant or wild-type STK11/LKB1 treated with radiotherapy, and assessed locoregional recurrence (LRR), distant metastasis rates, disease-free survival (DFS), and overall survival (OS), and we investigated the causal role of LKB1 in mediating radiotherapy resistance using isogenic pairs of NSCLC cell lines with LKB1 loss or gain. Results: In stage III patients, with 4 years median follow-up, STK11/LKB1 mutations were associated with higher LRR (P ¼ 0.0108), and shorter DFS (HR 2.530, P ¼ 0.0029) and OS (HR 2.198, P ¼ 0.0263). LKB1 loss promoted relative resistance to radiotherapy, which was dependent on the KEAP1/NRF2 pathway for redox homeostasis. Suppression of the KEAP1/NRF2 pathway via KEAP1 expression, or pharmacologic blockade of glutaminase (GLS) 1 sensitized LKB1-deficient tumors to radiotherapy. Conclusions: These data provide evidence that LKB1 loss is associated with LRR and poor clinical outcomes in patients with NSCLC treated with radiotherapy and that targeting the KEAP1/ NRF2 pathway or GLS inhibition are potential approaches to radiosensitize LKB1-deficient tumors.
AB - Purpose: Radiotherapy with or without chemotherapy is a mainstay of treatment for locally advanced non-small cell lung cancer (NSCLC), but no predictive markers are currently available to select patients who will benefit from these therapies. In this study, we investigated the association between alterations in STK11/LKB1, the second most common tumor suppressor in NSCLC, and response to radiotherapy as well as potential therapeutic approaches to improve outcomes. Experimental Design: We conducted a retrospective analysis of 194 patients with stage I-III NSCLC, including 164 stage III patients bearing mutant or wild-type STK11/LKB1 treated with radiotherapy, and assessed locoregional recurrence (LRR), distant metastasis rates, disease-free survival (DFS), and overall survival (OS), and we investigated the causal role of LKB1 in mediating radiotherapy resistance using isogenic pairs of NSCLC cell lines with LKB1 loss or gain. Results: In stage III patients, with 4 years median follow-up, STK11/LKB1 mutations were associated with higher LRR (P ¼ 0.0108), and shorter DFS (HR 2.530, P ¼ 0.0029) and OS (HR 2.198, P ¼ 0.0263). LKB1 loss promoted relative resistance to radiotherapy, which was dependent on the KEAP1/NRF2 pathway for redox homeostasis. Suppression of the KEAP1/NRF2 pathway via KEAP1 expression, or pharmacologic blockade of glutaminase (GLS) 1 sensitized LKB1-deficient tumors to radiotherapy. Conclusions: These data provide evidence that LKB1 loss is associated with LRR and poor clinical outcomes in patients with NSCLC treated with radiotherapy and that targeting the KEAP1/ NRF2 pathway or GLS inhibition are potential approaches to radiosensitize LKB1-deficient tumors.
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U2 - 10.1158/1078-0432.CCR-20-2859
DO - 10.1158/1078-0432.CCR-20-2859
M3 - Article
C2 - 33323404
AN - SCOPUS:85103342879
SN - 1078-0432
VL - 27
SP - 1720
EP - 1733
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 6
ER -