Adaptive resistance in tumors to anti-PD-1 therapy through re-immunosuppression by upregulation of GPNMB expression

2021 ◽  
Vol 101 ◽  
pp. 108199
Author(s):  
Xiaoqing Xu ◽  
Kun Xie ◽  
Bingyu Li ◽  
Lijun Xu ◽  
Lei Huang ◽  
...  
Keyword(s):  
Adaptive Resistance

Evaluation of Potent Isoquinoline-Based Thiosemicarbazone Antiproliferatives Against Solid Tumor Models

2019 ◽  
Author(s):  
Daniel Sun ◽  
Soumya Poddar ◽  
Roy D. Pan ◽  
Juno Van Valkenburgh ◽  
Ethan Rosser ◽  
...  
Keyword(s):  
Solid Tumor ◽  
Small Cell Lung Carcinoma ◽  
Single Agent ◽  
Resistance Mechanisms ◽  
Tumor Models ◽  
Cell Lung Carcinoma ◽  
Adaptive Resistance ◽  
Cancer Models ◽  
Nanomolar Range

The lead compound, an ⍺-N-heterocyclic carboxaldehyde thiosemicarbazone <b>HCT-13</b>, was highly potent against a panel of pancreatic, small cell lung carcinoma, and prostate cancer models, with IC<sub>90</sub> values in the low-to-mid nanomolar range.<b> </b>We show that the cytotoxicity of <b>HCT-13</b> is copper-dependent, that it acts as a copper ionophore, induces production of reactive oxygen species (ROS), and promotes mitochondrial dysfunction and S-phase arrest. Lastly, DNA damage response/replication stress response (DDR/RSR) pathways, specifically Ataxia-Telangiectasia Mutated (ATM) and Rad3-related protein kinase (ATR), were identified as actionable adaptive resistance mechanisms following <b>HCT-13 </b>treatment. Taken together, <b>HCT-13 </b>is potent against solid tumor models and warrants <i>in vivo</i> evaluation against aggressive tumor models, either as a single agent or as part of a combination therapy.

scholarly journals Overcoming Adaptive Resistance to KRAS and MEK Inhibitors by Co-targeting mTORC1/2 Complexes in Pancreatic Cancer

2020 ◽  
Vol 1 (8) ◽  
pp. 100131
Author(s):  
Wells S. Brown ◽  
Paul C. McDonald ◽  
Oksana Nemirovsky ◽  
Shannon Awrey ◽  
Shawn C. Chafe ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mek Inhibitors ◽  
Adaptive Resistance

E3 ubiquitin ligase Atrogin-1 mediates adaptive resistance to KIT-targeted inhibition in gastrointestinal stromal tumor

Oncogene ◽  
2021 ◽  
Author(s):  
Alfonso García-Valverde ◽  
Jordi Rosell ◽  
Sergi Sayols ◽  
David Gómez-Peregrina ◽  
Daniel F. Pilco-Janeta ◽  
...  
Keyword(s):  
Gastrointestinal Stromal Tumor ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Stromal Tumor ◽  
Adaptive Resistance ◽  
Targeted Inhibition

Abstract P071: Phosphoproteomics identifies Mig6 as a key mediator of adaptive resistance to ALK/ROS1 oncogene inhibition

2021 ◽  
Author(s):  
Nan Chen ◽  
Anh T. Le ◽  
Eric A. Welsh ◽  
Bin Fang ◽  
Eric B. Haura ◽  
...  
Keyword(s):  
Adaptive Resistance

scholarly journals Efficacy of Humanized Cefiderocol Exposures over 72 Hours against a Diverse Group of Gram-Negative Isolates in the Neutropenic Murine Thigh Infection Model

2018 ◽  
Vol 63 (2) ◽  
pp. e01040-18 ◽  
Author(s):  
Sean M. Stainton ◽  
Marguerite L. Monogue ◽  
Masakatsu Tsuji ◽  
Yoshinori Yamano ◽  
Roger Echols ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Acinetobacter Baumannii ◽  
Infection Model ◽  
Diverse Group ◽  
Gram Negative ◽  
Content Type ◽  
Adaptive Resistance

ABSTRACT Herein, we evaluated sustainability of humanized exposures of cefiderocol in vivo over 72 h against pathogens with cefiderocol MICs of 0.5 to 16 μg/ml in the neutropenic murine thigh model. In Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae displaying MICs of 0.5 to 8 μg/ml (n = 11), sustained kill was observed at 72 h among 9 isolates. Postexposure MICs revealed a single 2-dilution increase in one animal compared with controls (1/54 samples, 1.8%) at 72 h. Adaptive resistance during therapy was not observed.

Adaptive resistance to nitric oxide in motor neurons

1999 ◽  
Vol 26 (7-8) ◽  
pp. 978-986 ◽  
Author(s):  
Amy Bishop ◽  
John C Marquis ◽  
Neil R Cashman ◽  
Bruce Demple
Keyword(s):  
Nitric Oxide ◽  
Motor Neurons ◽  
Adaptive Resistance

scholarly journals Metabolomic adaptations and correlates of survival to immune checkpoint blockade

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Haoxin Li ◽  
Kevin Bullock ◽  
Carino Gurjao ◽  
David Braun ◽  
Sachet A. Shukla ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Resistance Mechanism ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Adaptive Resistance ◽  
Metabolic Monitoring ◽  
Pd1 Blockade ◽  
To Receive ◽  
Cell Death Protein

Abstract Despite remarkable success of immune checkpoint inhibitors, the majority of cancer patients have yet to receive durable benefits. Here, in order to investigate the metabolic alterations in response to immune checkpoint blockade, we comprehensively profile serum metabolites in advanced melanoma and renal cell carcinoma patients treated with nivolumab, an antibody against programmed cell death protein 1 (PD1). We identify serum kynurenine/tryptophan ratio increases as an adaptive resistance mechanism associated with worse overall survival. This advocates for patient stratification and metabolic monitoring in immunotherapy clinical trials including those combining PD1 blockade with indoleamine 2,3-dioxygenase/tryptophan 2,3-dioxygenase   (IDO/TDO) inhibitors.

scholarly journals Targeting KRAS: The Elephant in the Room of Epithelial Cancers

2021 ◽  
Vol 11 ◽  
Author(s):  
Valeria Merz ◽  
Marina Gaule ◽  
Camilla Zecchetto ◽  
Alessandro Cavaliere ◽  
Simona Casalino ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Small Cell Lung ◽  
Synthetic Lethal ◽  
Adaptive Resistance ◽  
Epithelial Cancers ◽  
Combination Strategies ◽  
Downstream Effectors ◽  
Cancer Types ◽  
Direct Targeting

Mutations of the proto-oncogene KRAS are the most frequent gain-of-function alterations found in cancer. KRAS is mutated in about 30% of all human tumors, but it could reach more than 90% in certain cancer types such as pancreatic adenocarcinoma. Although historically considered to be undruggable, a particular KRAS mutation, the G12C variant, has recently emerged as an actionable alteration especially in non-small cell lung cancer (NSCLC). KRASG12C and pan-KRAS inhibitors are being tested in clinical trials and have recently shown promising activity. Due to the difficulties in direct targeting of KRAS, other approaches are being explored. The inhibition of target upstream activators or downstream effectors of KRAS pathway has shown to be moderately effective given the evidence of emerging mechanisms of resistance. Various synthetic lethal partners of KRAS have recently being identified and the inhibition of some of those might prove to be successful in the future. The study of escape mechanisms to KRAS inhibition could support the utility of combination strategies in overcoming intrinsic and adaptive resistance and enhancing clinical benefit of KRASG12C inhibitors. Considering the role of the microenvironment in influencing tumor initiation and promotion, the immune tumor niche of KRAS mutant tumors has been deeply explored and characterized for its unique immunosuppressive skewing. However, a number of aspects remains to be fully understood, and modulating this tumor niche might revert the immunoresistance of KRAS mutant tumors. Synergistic associations of KRASG12C and immune checkpoint inhibitors are being tested.

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