bims-meluca 2023-03-05 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2023–03–05
nine papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

NRF2 activation induces NADH-reductive stress, providing a metabolic vulnerability in lung cancer.
Evaluation of KRASG12C inhibitor responses in novel murine KRASG12C lung cancer cell line models.
Novel mutant KRAS addiction signature predicts response to the combination of ERBB and MEK inhibitors in lung and pancreatic cancers.
Concurrent Mutations in STK11 and KEAP1 Cause Treatment Resistance in KRAS Wild-type Non-small-cell Lung Cancer.
Hyperoxia induces glucose metabolism reprogramming and intracellular acidification by suppressing MYC/MCT1 axis in lung cancer.
A Phase I/II Study of Necitumumab Plus Pembrolizumab, Nab-Paclitaxel, and Carboplatin for Previously Untreated Advanced Squamous Non-Small Cell Lung Cancer Study: (NEJ048A/NEXUS).
Hsa_circ_0070440 promotes lung adenocarcinoma progression by SLC7A11-mediated-ferroptosis.
Predictive value of 18F-FDG PET/CT for evaluating the response to hypofractionated radiotherapy combined with PD-1 blockade in non-small cell lung cancer.
MRTX-500 Phase 2 Trial: Sitravatinib With Nivolumab in Patients With Non-Squamous Non-Small Cell Lung Cancer Progressing On/After Checkpoint Inhibitor Therapy or Chemotherapy.

Cell Metab. 2023 Feb 22. pii: S1550-4131(23)00012-8. [Epub ahead of print]

NRF2 activation induces NADH-reductive stress, providing a metabolic vulnerability in lung cancer.

Tommy Weiss-Sadan, Maolin Ge, Makiko Hayashi, Magdy Gohar, Cong-Hui Yao, Adriaan de Groot, Stefan Harry, Alexander Carlin, Hannah Fischer, Lei Shi, Ting-Yu Wei, Charles H Adelmann, Konstantin Wolf, Tristan Vornbäumen, Benedikt R Dürr, Mariko Takahashi, Marianne Richter, Junbing Zhang, Tzu-Yi Yang, Vindhya Vijay, David E Fisher, Aaron N Hata, Marcia C Haigis, Raul Mostoslavsky, Nabeel Bardeesy, Thales Papagiannakopoulos, Liron Bar-Peled.

  Multiple cancers regulate oxidative stress by activating the transcription factor NRF2 through mutation of its negative regulator, KEAP1. NRF2 has been studied extensively in KEAP1-mutant cancers; however, the role of this pathway in cancers with wild-type KEAP1 remains poorly understood. To answer this question, we induced NRF2 via pharmacological inactivation of KEAP1 in a panel of 50+ non-small cell lung cancer cell lines. Unexpectedly, marked decreases in viability were observed in >13% of the cell lines-an effect that was rescued by NRF2 ablation. Genome-wide and targeted CRISPR screens revealed that NRF2 induces NADH-reductive stress, through the upregulation of the NAD+-consuming enzyme ALDH3A1. Leveraging these findings, we show that cells treated with KEAP1 inhibitors or those with endogenous KEAP1 mutations are selectively vulnerable to Complex I inhibition, which impairs NADH oxidation capacity and potentiates reductive stress. Thus, we identify reductive stress as a metabolic vulnerability in NRF2-activated lung cancers.

Keywords:  NADH/NAD(+); NRF2-KEAP1 pathway; functional genomic; non-small cell lung cancer; oxidative phosphorylation; reductive stress

DOI:  https://doi.org/10.1016/j.cmet.2023.01.012
Front Oncol. 2023 ;13 1094123

Evaluation of KRASG12C inhibitor responses in novel murine KRASG12C lung cancer cell line models.

Daniel J Sisler, Trista K Hinz, Anh T Le, Emily K Kleczko, Raphael A Nemenoff, Lynn E Heasley.

   Introduction: The KRAS(G12C) mutation is the most common genetic mutation in North American lung adenocarcinoma patients. Recently, direct inhibitors of the KRASG12C protein have been developed and demonstrate clinical response rates of 37-43%. Importantly, these agents fail to generate durable therapeutic responses with median progression-free survival of ~6.5 months.
Methods: To provide models for further preclinical improvement of these inhibitors, we generated three novel murine KRASG12C-driven lung cancer cell lines. The co-occurring NRASQ61L mutation in KRASG12C-positive LLC cells was deleted and the KRASG12V allele in CMT167 cells was edited to KRASG12C with CRISPR/Cas9 methods. Also, a novel murine KRASG12C line, mKRC.1, was established from a tumor generated in a genetically-engineered mouse model.
Results: The three lines exhibit similar in vitro sensitivities to KRASG12C inhibitors (MRTX-1257, MRTX-849, AMG-510), but distinct in vivo responses to MRTX-849 ranging from progressive growth with orthotopic LLC-NRAS KO tumors to modest shrinkage with mKRC.1 tumors. All three cell lines exhibited synergistic in vitro growth inhibition with combinations of MRTX-1257 and the SHP2/PTPN11 inhibitor, RMC-4550. Moreover, treatment with a MRTX-849/RMC-4550 combination yielded transient tumor shrinkage in orthotopic LLC-NRAS KO tumors propagated in syngeneic mice and durable shrinkage of mKRC.1 tumors. Notably, single-agent MRTX-849 activity in mKRC.1 tumors and the combination response in LLC-NRAS KO tumors was lost when the experiments were performed in athymic nu/nu mice, supporting a growing literature demonstrating a role for adaptive immunity in the response to this class of drugs.
Discussion: These new models of murine KRASG12C mutant lung cancer should prove valuable for identifying improved therapeutic combination strategies with KRASG12C inhibitors.

Keywords:  AMG-510; KRAS; MRTX-1257; lung cancer; orthotopic model

DOI:  https://doi.org/10.3389/fonc.2023.1094123
iScience. 2023 Mar 17. 26(3): 106082

Novel mutant KRAS addiction signature predicts response to the combination of ERBB and MEK inhibitors in lung and pancreatic cancers.

Katarzyna M Tyc, Aslamuzzaman Kazi, Alok Ranjan, Rui Wang, Said M Sebti.

  KRAS mutations are prevalent in pancreatic and lung cancers, but not all mutant (mt) KRAS tumors are addicted to mt KRAS. Here, we discovered a 30-gene transcriptome signature "KDS30" that encodes a novel EGFR/ERBB2-driven signaling network and predicts mt KRAS, but not NRAS or HRAS, oncogene addiction. High KDS30 tumors from mt KRAS lung and pancreatic cancer patients are enriched in genes upregulated by EGFR, ERBB2, mt KRAS or MEK. EGFR/ERBB2 (neratinib) and MEK (cobimetinib) inhibitor combination inhibits tumor growth and prolongs mouse survival in high, but not low, KDS30 mt KRAS lung and pancreatic xenografts, and is synergistic only in high KDS30 mt KRAS patient-derived organoids. Furthermore, mt KRAS high KDS30 lung and pancreatic cancer patients live significantly shorter lives than those with low KDS30. Thus, KDS30 can identify lung and pancreatic cancer patients whose tumors are addicted to mt KRAS, and predicts EGFR/ERBB2 and MEK inhibitor combination response.

Keywords:  Cancer; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2023.106082
Intern Med. 2023 Mar 01.

Concurrent Mutations in STK11 and KEAP1 Cause Treatment Resistance in KRAS Wild-type Non-small-cell Lung Cancer.

Masahiko Sumii, Masashi Namba, Kentaro Tokumo, Masami Yamauchi, Wataru Okamoto, Noboru Hattori, Kazuhiko Sugiyama.

  We herein report a patient with KRAS wild-type non-small-cell lung cancer (NSCLC) with concurrent STK11 and KEAP1 mutations. A 53-year-old man visited a local doctor with a complaint of left shoulder swelling and pain. He was diagnosed with NSCLC cT4N0M1c stage IVB. A comprehensive genome profile test revealed mutations in STK11 and KEAP1 but no KRAS mutations. The patient was refractory to radiotherapy, immunotherapy, and chemotherapy. Thus, STK11 and KEAP1 mutations can be considered resistance mutations that confer resistance to various anticancer therapies in KRAS wild-type NSCLC.

Keywords:  CGP test; KEAP1 mutation; KRAS mutation; STK11 mutation; non-small-cell lung cancer (NSCLC); therapy resistance

DOI:  https://doi.org/10.2169/internalmedicine.1110-22
Redox Biol. 2023 Feb 27. pii: S2213-2317(23)00048-4. [Epub ahead of print]61 102647

Hyperoxia induces glucose metabolism reprogramming and intracellular acidification by suppressing MYC/MCT1 axis in lung cancer.

Xiucheng Liu, Hao Qin, Li Zhang, Caili Jia, Zhixiang Chao, Xichun Qin, Hao Zhang, Chang Chen.

  The perils and promises of inspiratory hyperoxia (IH) in oncology are still controversial, especially for patients with lung cancer. Increasing evidence shows that hyperoxia exposure is relevant to the tumor microenvironment. However, the detailed role of IH on the acid-base homeostasis of lung cancer cells remains unclear. In this study, the effects of 60% oxygen exposure on intra- and extracellular pH were systematically evaluated in H1299 and A549 cells. Our data indicate that hyperoxia exposure reduces intracellular pH, which might be expected to reduce the proliferation, invasion, and epithelial-to-mesenchymal transition of lung cancer cells. RNA sequencing, Western blot, and PCR analysis reveal that monocarboxylate transporter 1 (MCT1) mediates intracellular lactate accumulation and intracellular acidification of H1299 and A549 cells at 60% oxygen exposure. In vivo studies further demonstrate that MCT1 knockdown dramatically reduces lung cancer growth, invasion, and metastasis. The results of luciferase and ChIP-qPCR assays further confirm that MYC is a transcription factor of MCT1, and PCR and Western blot assays confirm that MYC is downregulated under hyperoxic conditions. Collectively, our data reveal that hyperoxia can suppress the MYC/MCT1 axis and cause the accumulation of lactate and intracellular acidification, thereby retarding tumor growth and metastasis.

Keywords:  Acid-base hemostasis; Inspiratory hyperoxia; Lung cancer; Monocarboxylate transporter 1

DOI:  https://doi.org/10.1016/j.redox.2023.102647
Clin Lung Cancer. 2023 Feb 01. pii: S1525-7304(23)00010-4. [Epub ahead of print]

A Phase I/II Study of Necitumumab Plus Pembrolizumab, Nab-Paclitaxel, and Carboplatin for Previously Untreated Advanced Squamous Non-Small Cell Lung Cancer Study: (NEJ048A/NEXUS).

Akihiko Miyanaga, Hajime Asahina, Satoshi Watanabe, Takehito Shukuya, Yukari Tsubata, Yukio Hosomi, Shunichi Sugawara, Makoto Maemondo, Tetsuya Okano, Satoshi Morita, Kotone Matsuyama, Kunihiko Kobayashi, Masahiro Seike.

   BACKGROUND: Platinum-based combination therapy plus a programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) inhibitor is a standard treatment for patients with stage IV non-small cell lung cancer. However, necitumumab is used with gemcitabine and cisplatin as a first-line treatment option for squamous cell lung cancer (SqCLC). Furthermore, the combination of necitumumab with immune checkpoint inhibitors has the potential to enhance tumor immunity and improve the therapeutic effect. Thus, we planned and initiated this phase I/II study to evaluate the safety and efficacy of necitumumab plus pembrolizumab, nanoparticle albumin-bound (nab)-paclitaxel), and carboplatin therapy for patients with previously untreated SqCLC.
PATIENTS AND METHODS: In phase I, the primary endpoint is the tolerability and recommended dose of necitumumab combined with pembrolizumab plus nab-paclitaxel and carboplatin. In phase II, the primary endpoint is the overall response rate. Secondary endpoints are disease control rate, progression-free survival, overall survival, and safety. Forty-two patients will be enrolled in phase II.
CONCLUSION: This is the first study to investigate the efficacy and safety of necitumumab plus pembrolizumab combined with platinum-based chemotherapy in patients with previously untreated SqCLC.

Keywords:  Chemotherapy; Clinical trial; Phase I/II; necitumumab; squamous NSCLC

DOI:  https://doi.org/10.1016/j.cllc.2023.01.008
Histol Histopathol. 2023 Feb 22. 18597

Hsa_circ_0070440 promotes lung adenocarcinoma progression by SLC7A11-mediated-ferroptosis.

Yong Zhao, Qichen Cui, Jian Shen, Weihong Shen, Yuan Weng.

BACKGROUND: Circular RNA (circRNA) has recently emerged as having a key role in cancer initiation and progression. A prior study exhibited that hsa_circ_0070440 (circ_0070440) was significantly up-regulated in lung cancer cells, but the role and molecular mechanism of circ_0070440 during lung adenocarcinoma (LUAD) development remain unclear.
METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR), Reverse transcription-PCR (RT-PCR), RNase R digestion, and Nuclear/cytoplasmic fractionation assay were employed to validate circ_0070440. Proliferation, apoptosis, viability, and ferrous iron level were measured by colony formation, 5-Ethynyl-2'-deoxyuridine (EdU), Annexin V-FITC/PI double staining, Cell Counting Kit-8 (CCK-8), and iron assay in LUAD cells. A xenograft mouse model was used for tumor growth in vivo. Western blot (WB) and immunohistochemistry (IHC) assays were utilized to determine the expression of solute carrier family 7 member 11 (SLC7A11), c-myc, and bcl-xL. The interactions between the circ_0070440/SLC7A11 axis and miR-485-5p were verified by RNA pull-down assay and dual-luciferase reporter assay.
RESULTS: Circ_0070440 was significantly up-regulated in LUAD cells. Knockdown of circ_0070440 inhibited growth and promoted both apoptosis and ferroptosis of LUAD cells. Moreover, our results showed that circ_0070440 contributed to malignant progression and suppressed ferroptosis of LUAD by sponging miR-485-5p and upregulating SLC7A11 expression. Furthermore, circ_0070440 and SLC7A11 levels were up-regulated, and the miR-485-5p level was more down-regulated in the tumor tissues than in normal tissues of LUAD patients.
CONCLUSION: Circ_0070440 modulated LUAD malignant progression and ferroptosis via targeting SLC7A11, implying a significant role of the circ_0070440/miR-485-5p/SLC7A11 axis in the diagnosis and treatment of LUAD.

DOI: https://doi.org/10.14670/HH-18-597
Front Immunol. 2023 ;14 1034416

Predictive value of 18F-FDG PET/CT for evaluating the response to hypofractionated radiotherapy combined with PD-1 blockade in non-small cell lung cancer.

Shan Tang, Yan Zhang, Yunfei Li, Yan Zhang, Yuke Xu, Haoyuan Ding, Yue Chen, Peirong Ren, Hua Ye, Shaozhi Fu, Sheng Lin.

   Purpose: This retrospective study aimed to investigate 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography/computed tomography (PET/CT) as a predictor of response to hypofractionated radiotherapy (HFRT) combined with programmed cell death-1 (PD-1) blockade for lung cancer.
Methods: We included 41 patients with advanced non-small cell lung cancer (NSCLC) in this study. PET/CT was performed before (SCAN-0) and one month (SCAN-1), three months (SCAN-2), and six months (SCAN-3) after treatment. Using the European Organization for Research and Treatment of Cancer 1999 criteria and PET response criteria in solid tumors, treatment responses were classified as complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), or progressive metabolic disease (PMD). Patients were further categorized as those with metabolic benefits (MB; SMD, PMR, and CMR) and those without MBs (NO-MB; PMD). We analyzed the prognosis and overall survival (OS) of patients with new visceral/bone lesions during treatment. Based on the findings, we generated a nomogram to predict survival. Receiver operating characteristics and calibration curves were used to evaluate the accuracy of the prediction model.
Results: The mean OS based on SCANs 1, 2, and 3 was significantly higher in patients with MB and those without new visceral/bone lesions. The prediction nomogram for survival had a high area under the curve and a high predictive value based on the receiver operating characteristics and calibration curves.
Conclusion: 18FDG-PET/CT has the potential to predict the outcomes of HFRT combined with PD-1 blockade in NSCLC. Therefore, we recommend using a nomogram to predict patient survival.

Keywords:  18F-FDG PET/CT; NSCLC; PD-1 blockade; hypofractionated radiotherapy; predictive value

DOI:  https://doi.org/10.3389/fimmu.2023.1034416
J Thorac Oncol. 2023 Feb 24. pii: S1556-0864(23)00158-2. [Epub ahead of print]

MRTX-500 Phase 2 Trial: Sitravatinib With Nivolumab in Patients With Non-Squamous Non-Small Cell Lung Cancer Progressing On/After Checkpoint Inhibitor Therapy or Chemotherapy.

Kai He, David Berz, Shirish M Gadgeel, Wade T Iams, Debora S Bruno, Collin M Blakely, Alexander I Spira, Manish R Patel, David M Waterhouse, Donald A Richards, Anthony Pham, Robert Jotte, David S Hong, Edward B Garon, Anne Traynor, Peter Olson, Lisa Latven, Xiaohong Yan, Ronald Shazer, Ticiana A Leal.

   INTRODUCTION: Sitravatinib, a receptor tyrosine kinase inhibitor targeting TAM receptors and VEGFR2, can shift the tumor microenvironment towards an immunostimulatory state. Combining sitravatinib with checkpoint inhibitors (CPI) may augment antitumor activity.
METHODS: The phase 2 MRTX-500 study evaluated sitravatinib (120 mg daily) with nivolumab (every 2/4 weeks) in patients with advanced non-squamous non-small cell lung cancer (NSCLC) who progressed on/after prior CPI (CPI-experienced) or chemotherapy (CPI-naïve). CPI-experienced patients had prior clinical benefit (PCB; complete/partial response or stable disease for ≥12 weeks then disease progression) or no PCB (NPCB) from CPI. Primary endpoint was objective response rate (ORR); secondary objectives included safety and secondary efficacy endpoints.
RESULTS: Overall, 124 CPI-experienced (NPCB, n = 35; PCB, n = 89) and 32 CPI-naïve patients were treated. Investigator-assessed ORR was 11.4% in patients with NPCB, 16.9% with PCB, and 25.0% in CPI-naïve. Median progression-free survival was 3.7, 5.6, and 7.1 months with NPCB, PCB, and CPI-naïve, respectively; median overall survival was 7.9 and 13.6 months with NPCB and PCB, respectively (not reached in CPI-naïve patients; median follow-up 20.4 months). Overall, (N = 156), any grade treatment-related adverse events (TRAEs) occurred in 93.6%; grade 3/4 in 58.3%. One grade 5 TRAE occurred in a CPI-naïve patient. TRAEs led to treatment discontinuation in 14.1% and dose reduction/interruption in 42.9%. Biomarker analyses supported an immunostimulatory mechanism of action.
CONCLUSIONS: Sitravatinib with nivolumab had a manageable safety profile. Although ORR was not met, this combination demonstrated antitumor activity and encouraging survival in CPI-experienced patients with non-squamous NSCLC.

Keywords:  NSCLC; antitumor activity; nivolumab; sitravatinib; tyrosine kinase inhibitor

DOI:  https://doi.org/10.1016/j.jtho.2023.02.016