Cancer Research and Treatment

Original Article

Lung and Thoracic cancer

Combination of the LARS1 Inhibitor, BC-LI-0186 with a MEK1/2 Inhibitor Enhances the Anti-Tumor Effect in Non–Small Cell Lung Cancer: Sang Hoon Lee, Eun Young Kim, Jung Min Han, Gyoonhee Han, Yoon Soo Chang; Cancer Res Treat. 2023;55(3):851-864. Published online March 20, 2023; DOI: https://doi.org/10.4143/crt.2022.1527

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Purpose
The mammalian target of rapamycin complex 1 (mTORC1) regulates cell growth and proliferation by growth factor coordination and amino acid availability. Leucyl-tRNA synthetase 1 (LARS1) senses the intracellular leucine concentration and mediates amino acid-induced activation of mTORC1. Thus, LARS1 inhibition could be useful in cancer treatment. However, the fact that mTORC1 can be stimulated by various growth factors and amino acids suggests that LARS1 inhibition alone has limitations in inhibiting cell growth and proliferation. We investigated the combined effects of BC-LI-0186, a LARS1 inhibitor, and trametinib, an MEK inhibitor, on non–small cell lung cancer (NSCLC).
Materials and Methods
Protein expression and phosphorylation were observed by immunoblotting, and genes differentially expressed between BC-LI-0186–sensitive and –resistant cells were identified by RNA sequencing. The combined effect of the two drugs was inferred from the combination index values and a xenograft model.
Results
LARS1 expression was positively correlated with mTORC1 in NSCLC cell lines. BC-LI-0186 treatment of A549 and H460 cells maintained in media supplemented with fetal bovine serum revealed paradoxical phosphorylation of S6 and activation of mitogen- activated protein kinase (MAPK) signaling. Compared with BC-LI-0186–sensitive cells, –resistant cells showed enrichment of the MAPK gene set. The combination of trametinib and BC-LI-0186 inhibited the phosphorylation of S6, MEK, and extracellular signal-regulated kinase and their synergistic effects were confirmed in a mouse xenograft model.
Conclusion
The combination of BC-LI-0186 and trametinib inhibited the non-canonical mTORC1-activating function of LARS1. Our study demonstrated a new therapeutic approach for NSCLC without targetable driver mutations.

Citations

Citations to this article as recorded by

LARS1 is a Prognostic Biomarker and Exhibits a Correlation with Immune Infiltrates in Hepatocellular Carcinoma
Longfei Fan, Zhongqiang Qin, Di Wu, Yunchuan Yang, Yigang Zhang, Bo Xie, Jingyu Qian, Jianzhu Wei, Zhaoying Wang, Peipei Yang, Zhen Qian, Mu Yuan, Ziyi Zhu, Yulin Tan, Yi Tan
International Journal of General Medicine.2024; Volume 17: 2203. CrossRef
Personalizing Therapy Outcomes through Mitogen-Activated Protein Kinase Pathway Inhibition in Non-Small Cell Lung Cancer
Hasan Alsharoh, Paul Chiroi, Ekaterina Isachesku, Radu Andrei Tanasa, Ovidiu-Laurean Pop, Radu Pirlog, Ioana Berindan-Neagoe
Biomedicines.2024; 12(7): 1489. CrossRef
UCHL1 Overexpression Is Related to the Aggressive Phenotype of Non-small Cell Lung Cancer
Chi Young Kim, Eun Hye Lee, Se Hyun Kwak, Sang Hoon Lee, Eun Young Kim, Min Kyoung Park, Yoon Jin Cha, Yoon Soo Chang
Tuberculosis and Respiratory Diseases.2024; 87(4): 494. CrossRef

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Case Report

Unusual Manifestation of Intravascular Large B-Cell Lymphoma: Severe Hypercalcemia with Parathyroid Hormone-Related Protein: Jung Min Ha, Eun Kim, Woo Joo Lee, Ji-Won Hwang, Sehyo Yune, Young Hyeh Ko, Joon Young Choi, Seok Jin Kim, Won Seog Kim; Cancer Res Treat. 2014;46(3):307-311. Published online July 15, 2014; DOI: https://doi.org/10.4143/crt.2014.46.3.307

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Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of non-Hodgkin lymphoma. It usually presents with nonspecific symptoms, such as fever, rather than with overt lymphadenopathy. Reports of hypercalcemia, as the initial presentation of IVLBCL, are limited in the literature, despite it being a well-known complication of various solid cancers. We present a 68-year-old male with severe hypercalcemia and increased levels of serum parathyroid hormone-related protein. He was diagnosed with IVLBCL, involving the bone marrow and spleen, and was successfully treated with rituximab-containing chemotherapy. A few previous case reports have shown hypercalcemia in patients with IVLBCL. Much like our case, previous cases with hypercalcemia had advanced diseases, including bone marrow invasion. Although it was an extremely rare manifestation of IVLBCL, we suggest that IVLBCL should be a part of the differential diagnosis in patients with unexplained hypercalcemia. Therefore, an active work-up might be recommended, including positron emission tomography/ computed tomography scan and bone marrow examination, which may be useful for early diagnosis.

Citations

Citations to this article as recorded by

Case Report: Intravascular Large B-Cell Lymphoma: A Clinicopathologic Study of Four Cases With Review of Additional 331 Cases in the Literature
Yingying Han, Qingjiao Li, Dan Wang, Lushan Peng, Tao Huang, Chunlin Ou, Keda Yang, Junpu Wang
Frontiers in Oncology.2022;[Epub] CrossRef
Imaging Features and Prognostic Value of FDG PET/CT in Patients with Intravascular Large B-Cell Lymphoma
Chae Hong Lim, Sang Eun Yoon, Won Seog Kim, Kyung-Han Lee, Seok Jin Kim
Cancer Management and Research.2021; Volume 13: 7289. CrossRef
Missed diagnosis of lymphoma presenting with humoral hypercalcemia of malignancy due to cessation of oncological workup after negative computed tomography scans
Ellery Altshuler, Mahmoud Aryan, William King, Rolando Otero
BMJ Case Reports.2021; 14(12): e246669. CrossRef
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Silvia Uccella, Francesca Magnoli, Cristina Amaglio, Fausto Sessa, Stefano La Rosa
Diagnostic Histopathology.2019; 25(5): 166. CrossRef
Diagnosis of intravascular large B cell lymphoma: novel insights into clinicopathological features from 42 patients at a single institution over 20 years
Kosei Matsue, Yoshiaki Abe, Kentaro Narita, Hiroki Kobayashi, Akihiro Kitadate, Masami Takeuchi, Daisuke Miura, Kengo Takeuchi
British Journal of Haematology.2019; 187(3): 328. CrossRef
Klinische und pathologische Charakteristika intravaskulärer Lymphome
L. Abraham, H. Kreipe, P. Raab, K. Hussein
Der Pathologe.2018; 39(3): 242. CrossRef
Primary Bone Marrow B-Cell Lymphoma Undetected by Multiple Imaging Modalities That Initially Presented with Hypercalcemia
Jin Sae Yoo, Juwon Kim, Hyeong Ju Kwon, Jung Soo Lim
Case Reports in Endocrinology.2018; 2018: 1. CrossRef
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Wiener klinisches Magazin.2018; 21(5): 206. CrossRef

12,233 View
67 Download
7 Web of Science
8 Crossref

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