bims-meluca 2021-01-24 papers

Lung Cancer. 2021 Jan 02. pii: S0169-5002(20)30760-1. [Epub ahead of print]153 73-80

Loss of wild type KRAS in KRASMUT lung adenocarcinoma is associated with cancer mortality and confers sensitivity to FASN inhibitors.

Liu Y, Gao GF, Minna JD, Williams NS, Westover KD.

OBJECTIVES: Wild type RAS (RASWT) suppresses the function of oncogenic RAS mutants (RASMUT) in laboratory models. Loss of RASWT, which we termed loss of heterozygosity (LOH) for any RAS (LAR) or LAKR in the context of KRAS (LOH at KRAS), is found in patients with RASMUT cancers. However, the incidence and prognostic significance of LAR has not been studied in modern patient cohorts. LAR or LAKR in RASMUT cancers is attractive as a potential biomarker for targeted therapy.MATERIALS AND METHODS: We evaluated for associations between LAKR and cancer mortality in patients with KRASMUT lung adenocarcinoma (LUAD). We also evaluated for associations between LAKR and the metabolic state of cancer cell lines, given that KRAS has been shown to regulate fatty acid synthesis. In line with this, we investigated fatty acid synthase (FASN) inhibitors as potential therapies for KRASMUT LAKR, including combination strategies involving clinical KRASG12C and FASN inhibitors.
RESULTS: 24 % of patients with KRASMUT LUAD showed LAKR. KRASMUT LAKR cases had a median survival of 16 vs. 30 months in KRASMUT non-LAKR (p =  0.017) and LAKR was independently associated with death in this cohort (p =  0.011). We also found that KRASMUT LUAD cell lines with LAKR contained elevated levels of FASN and fatty acids relative to non-LAKR cell lines. KRASMUT LUAD cells with LAKR showed higher sensitivity to treatment with FASN inhibitors than those without. FASN inhibitors such as TVB-3664 showed synergistic effects with the KRASG12C inhibitor MRTX849 in LUAD cells with KRASG12C and LAKR, including an in vivo trial using a xenograft model.
CONCLUSIONS: LAKR in KRASMUT cancers may represent an independent negative prognostic factor for patients with KRASMUT LUAD. It also predicts for response to treatment with FASN inhibitors. Prospective testing of combination therapies including KRASG12C and FASN inhibitors in patients with KRASG12C LAKR is warranted.

Keywords: KRAS; Lung adenocarcinoma; RAS; loss of heterozygosity

DOI: https://doi.org/10.1016/j.lungcan.2020.12.032

Theranostics. 2021 ;11(6): 2860-2875

Cisplatin-resistant NSCLC cells induced by hypoxia transmit resistance to sensitive cells through exosomal PKM2.

Wang D, Zhao C, Xu F, Zhang A, Jin M, Zhang K, Liu L, Hua Q, Zhao J, Liu J, Yang H, Huang G.

Hypoxia is commonly observed in solid tumors and contributes to the resistance of DNA damage drugs. However, the mechanisms behind this resistance are still unclear. In this study, we aimed to explore the effects of hypoxia-induced exosomes on non-small cell lung cancer (NSCLC). Methods: NSCLC cells were subjected to either normoxic or hypoxic conditions to assess cell survival and changes in the expression levels of key proteins. Comparative proteomics were performed to identify exosomal PKM2 in normoxic or hypoxic cisplatin-resistant NSCLC cells-derived exosomes. Functions of hypoxia induced-exosomal PKM2 in promoting cisplatin resistance to NSCLC cells were evaluated both in vitro and in vivo experiments and the molecular mechanisms of hypoxia induced-exosomal PKM2 were demonstrated using flow cytometry, immunoblotting, oxidative stress detection and histological examination. A series of in vitro experiments were performed to evaluate the function of hypoxia-induced exosomes on cancer-associated fibroblasts (CAFs). Results: Hypoxia exacerbated the cisplatin resistance in lung cancer cells due to the increased expression of PKM2 that was observed in the exosomes secreted by hypoxic cisplatin-resistance cells. We identified that hypoxia-induced exosomal PKM2 transmitted cisplatin-resistance to sensitive NSCLC cells in vitro and in vivo. Mechanistically, hypoxia-induced exosomal PKM2 promoted glycolysis in NSCLC cells to produce reductive metabolites, which may neutralize reactive oxygen species (ROS) induced by cisplatin. Additionally, hypoxia-induced exosomal PKM2 inhibited apoptosis in a PKM2-BCL2-dependent manner. Moreover, hypoxia-induced exosomal PKM2 reprogrammed CAFs to create an acidic microenvironment promoting NSCLC cells proliferation and cisplatin resistance. Conclusions: Our findings revealed that hypoxia-induced exosomes transmit cisplatin resistance to sensitive NSCLC cells by delivering PKM2. Exosomal PKM2 may serve as a promising biomarker and therapeutic target for cisplatin resistance in NSCLC.

Keywords: CAFs; Drug-resistance; Exosomes; NSCLC; PKM2

DOI: https://doi.org/10.7150/thno.51797

Front Cell Dev Biol. 2020 ;8 610903

The Role of Anti-angiogenesis in the Treatment Landscape of Non-small Cell Lung Cancer - New Combinational Approaches and Strategies of Neovessel Inhibition.

Daum S, Hagen H, Naismith E, Wolf D, Pircher A.

Tumor progression depends primarily on vascular supply, which is facilitated by angiogenic activity within the malignant tissue. Non-small cell lung cancer (NSCLC) is a highly vascularized tumor, and inhibition of angiogenesis was projected to be a promising therapeutic approach. Over a decade ago, the first anti-angiogenic agents were approved for advanced stage NSCLC patients, however, they only produced a marginal clinical benefit. Explanations why anti-angiogenic therapies only show modest effects include the highly adaptive tumor microenvironment (TME) as well as the less understood characteristics of the tumor vasculature. Today, advanced methods of in-depth characterization of the NSCLC TME by single cell RNA sequencing (scRNA-Seq) and preclinical observations enable a detailed characterization of individual cancer landscapes, allowing new aspects for a more individualized inhibition of angiogenesis to be identified. Furthermore, the tumor vasculature itself is composed of several cellular subtypes, which closely interact with other cellular components of the TME, and show distinct biological functions such as immune regulation, proliferation, and organization of the extracellular matrix. With these new insights, combinational approaches including chemotherapy, anti- angiogenic and immunotherapy can be developed to yield a more target-oriented anti-tumor treatment in NSCLC. Recently, anti-angiogenic agents were also shown to induce the formation of high endothelial venules (HEVs), which are essential for the formation of tertiary lymphoid structures, and key components in triggering anti-tumor immunity. In this review, we will summarize the current knowledge of tumor-angiogenesis and corresponding anti-angiogenic therapies, as well as new aspects concerning characterization of tumor-associated vessels and the resulting new strategies for anti-angiogenic therapies and vessel inhibition in NSCLC. We will further discuss why anti-angiogenic therapies form an interesting backbone strategy for combinational therapies and how anti-angiogenic approaches could be further developed in a more personalized tumor-oriented fashion with focus on NSCLC.

Keywords: angiogenesis; combinational therapy; immunotherapy; non-small cell lung cancer; tumor endothelial cells; tumor microenvironment; vascular endothelial growth factor

DOI: https://doi.org/10.3389/fcell.2020.610903