<i>STK11</i>/LKB1 Mutations in NSCLC Are Associated with KEAP1/NRF2-Dependent Radiotherapy Resistance Targetable by Glutaminase Inhibition

Sitthideatphaiboon, Piyada; Galán-Cobo, Ana; Negrão, Marcelo V.; Qu, Xiao; Poteete, Alissa; Zhang, Fahao; Liu, Diane D.; Lewis, Whitney E.; Kemp, Haley N.; Lewis, Jeff; Rinsurongkawong, Waree; Giri, Uma; Lee, J. Jack; Zhang, Jianjun; Roth, Jack A.; Swisher, Stephen G.; Heymach, John V.

doi:10.1158/1078-0432.ccr-20-2859

Cited by 56 publications

(37 citation statements)

References 50 publications

(81 reference statements)

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“…Locally advanced NSCLC is often treated with radiotherapy with or without chemotherapy. A recent study by Sitthideatphaiboon et al investigated the association between STK11 mutations in stage III NSCLC and outcomes after radiotherapy in a population of 194 patients [ 47 ]. After a median follow-up of four years, the study found that STK11 mutations were associated with a significantly higher locoregional recurrence rate (LRR, p=0.0108) and shorter disease-free survival (DFS; HR 2.53; [1.37-4.65], p=0.002).…”

Section: Reviewmentioning

confidence: 99%

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Unraveling the Role of STK11/LKB1 in Non-small Cell Lung Cancer

Sumbly¹,

Landry²

2022

Cureus

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There are two major groups of lung cancer: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLCs can be further separated into three different categories: lung adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Pulmonary adenocarcinomas represent nearly half of all lung cancer cases and are known to be caused by smoking, certain occupational exposures, and specific genetic mutations. Scientists have noticed that most NSCLCs are driven by defects in the following genes: EGFR, BRAF, ALK, MET, and HER. Abnormalities in the STK11/LKB1 gene have also been shown to induce lung adenocarcinoma. LKB1-deficient cancer cells contain an overactive AMPK "energy sensor," which inhibits cellular death and promotes glucose, lipid, and protein synthesis via the mTOR protein complex. Studies have also discovered that the loss of STK11/LKB1 favors oncogenesis by creating an immunosuppressive environment for tumors to grow and accelerate events such as angiogenesis, epithelial-mesenchymal transition (EMT), and cell polarity destabilization. STK11/LKB1-mutant lung cancers are currently treated with radiotherapy with or without chemotherapy. Recent clinical trials studying the effects of glutaminase inhibitors, mTOR inhibitors, and anti-PD-L1 therapy in lung cancer patients have yielded promising results. This narrative review provides an overview of the STK11/LKB1 gene and its role in cancer development. Additionally, a summary of the LKB1/APMK/mTOR is provided.

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Section: Reviewmentioning

confidence: 99%

“…LKB1 loss increases downstream production of NRF2, which, in turn, reduces reactive oxygen species (ROS) levels. Because radiation treatment relies on the destruction of tumor cells via intracellular ROS damage, tumor cells with these mutations can resist high levels of treatment [ 47 ].…”

Section: Reviewmentioning

confidence: 99%

Unraveling the Role of STK11/LKB1 in Non-small Cell Lung Cancer

Sumbly¹,

Landry²

2022

Cureus

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“…Tumor cells, in contrast to non-transformed cells, frequently harbor mutations in check point genes and fail to halt the cell cycle to initiate the repair of damaged DNA 50–53 . Mutations in oncogenes, such as KRAS 54 ; and subsets of loss-of-function mutations in tumor suppressors, such as FBXW7 44, 55 or STK11 56 , can cause resistance to DNA damage based therapies. Identification of exploitable ‘bottlenecks’ for tumor cell survival might be an option to advance our current treatment options.…”

Section: Discussionmentioning

confidence: 99%

PTEN mutant NSCLC require ATM to suppress pro-apoptotic signalling and evade radiotherapy

Fischer

Hartmann

Reissland

et al. 2021

Preprint

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Background: Despite advances in treatment of patients with non-small cell lung cancer, carriers of certain genetic alterations are prone to failure. One such factor frequently mutated, is the tumor suppressor PTEN. These tumors are supposed to be more resistant to radiation, chemo- and immunotherapy. Methods: Using CRISPR genome editing, we deleted PTEN in a human tracheal stem cell-like cell line as well generated primary murine NSCLC, proficient or deficient for Pten, in vivo. These models were used to verify the impact of PTEN loss in vitro and in vivo by immunohistochemical staining, western blot and RNA-Sequencing. Radiation sensitivity was assessed by colony formation and growth assays. To elucidate putative treatment options, identified via the molecular characterisation, PTEN pro- and deficient cells were treated with PI3K/mTOR/DNA-PK-inhibitor PI-103 or the ATM-inhibitors KU-60019 und AZD 1390. Changes in radiation sensitivity were assessed by colony-formation assay, FACS, western-blot, phospho-proteomic mass spectrometry and ex vivo lung slice cultures. Results: We demonstrate that loss of PTEN led to altered expression of transcriptional programs which directly regulate therapy resistance, resulting in establishment of radiation resistance. While PTEN-deficient tumor cells were not dependent on DNA PK for IR resistance nor activated ATR during IR, they showed a significant dependence for the DNA damage kinase ATM. Pharmacologic inhibition of ATM, via KU-60019 and AZD1390 at non-toxic doses, restored and even synergized with IR in PTEN-deficient human and murine NSCLC cells as well in a multicellular organotypic ex vivo tumor model. Conclusion: PTEN tumors are addicted to ATM to detect and repair radiation induced DNA damage. This creates an exploitable bottleneck. At least in cellulo and ex vivo we show that low concentration of ATM inhibitor is able to synergise with IR to treat PTEN-deficient tumors in genetically well-defined IR resistant lung cancer models.

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“…31,32 In lung cancers, Nrf2 gain-of-function mutations often occur, and higher intratumoral levels of Nrf2 are associated with poor clinical outcomes. [33][34][35][36] However, currently, little evidence is available on the effect of DADS on Nrf2 expression in response to radiation. Whether and how DADS influences IR-induced migration and invasion in NSCLC is still unknown.…”

Section: Introductionmentioning

confidence: 99%

Diallyl Disulfide Attenuates Ionizing Radiation-Induced Migration and Invasion by Suppressing Nrf2 Signaling in Non–small-Cell Lung Cancer

Huang

Tang

et al. 2021

Dose-Response

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Non–small-cell lung cancer (NSCLC) is the leading cause of cancer-associated deaths. Radiotherapy remains the primary treatment method for NSCLC. Despite great advances in radiotherapy techniques and modalities, recurrence and resistance still limit therapeutic success, even low-dose ionizing radiation (IR) can induce the migration and invasion. Diallyl disulfide (DADS), a bioactive component extracted from garlic, exhibits a wide spectrum of biological activities including antitumor effects. However, the effect of DADS on IR-induced migration and invasion remains unclear. The present study reported that IR significantly promoted the migration and invasion of A549 cells. Pretreatment with 40 μM DADS enhanced the radiosensitivity of A549 cells and attenuated IR-induced migration and invasion. In addition, 40 μM DADS inhibited migration-related protein matrix metalloproteinase-2 and 9 (MMP-2/9) expression and suppressed IR-aggravated EMT by the upregulation of the epithelial marker, E-cadherin, and downregulation of the mesenchymal marker, N-cadherin, in A549 cells. Furthermore, DADS was found to inhibit the activation of Nrf2 signaling. Based on our previous results that knockdown of Nrf2 by siRNA suppressed IR-induced migration and invasion in A549 cells, we speculated that DADS attenuated IR-induced migration and invasion by suppressing the activation of Nrf2 signaling in A549 cells.

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STK11/LKB1 Mutations in NSCLC Are Associated with KEAP1/NRF2-Dependent Radiotherapy Resistance Targetable by Glutaminase Inhibition

Abstract: Purpose: Radiotherapy (RT) 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 *

Cited by 56 publications

References 50 publications

Unraveling the Role of STK11/LKB1 in Non-small Cell Lung Cancer

Unraveling the Role of STK11/LKB1 in Non-small Cell Lung Cancer

PTEN mutant NSCLC require ATM to suppress pro-apoptotic signalling and evade radiotherapy

Diallyl Disulfide Attenuates Ionizing Radiation-Induced Migration and Invasion by Suppressing Nrf2 Signaling in Non–small-Cell Lung Cancer

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