Antagonism of EGFR and Notch limits resistance to EGFR inhibitors and radiation by decreasing tumor-initiating cell frequency

Hu, Shi; Fu, Wenyan; Li, Tian; Yuan, Qingning; Wang, Feifei; Lv, Gaojian; Lv, Yuanyuan; Fan, Xiaoyan; Shen, Yan; Lin, Fangxing; Tang, Ying; Ye, Xuting; Yang, Yue; Lei, Changhai

doi:10.1126/scitranslmed.aag0339

Cited by 62 publications

(54 citation statements)

References 53 publications

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“…Adc, bsAb and cAR-T technologies (166)(167)(168)(169) have been applied to enhance the benefits of therapeutic mAbs in patients with cancer. Notch-related investigational biologics include Adcs targeting dLL3 [rovalpituzumab tesirine (Rova-T)] (170-172) and NOTcH3 (PF-06650808) (173); bsAbs targeting dLL3/cd3 (AMG 757) (174), dLL4/VEGF (ABT-165 and navicixizumab) (175,176) and NOTcH2/3/EGFR (cT16 and PTG12) (177,178); and cAR-Ts targeting dLL3 (AMG 119) (179) ( Table I). A phase I clinical trial of the anti-dLL4/VEGF bsAb navicixizumab in 66 patients with solid tumors (registration no.…”

Section: Therapeutics Targeting Notch Signaling Cascadesmentioning

confidence: 99%

Precision medicine for human cancers with Notch signaling dysregulation (Review)

Katoh¹,

2019

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NOTcH1, NOTcH2, NOTcH3 and NOTcH4 are transmembrane receptors that transduce juxtacrine signals of the delta-like canonical Notch ligand (dLL)1, dLL3, dLL4, jagged canonical Notch ligand (JAG)1 and JAG2. canonical Notch signaling activates the transcription of BMI1 proto-oncogene polycomb ring finger, cyclin D1, CD44, cyclin dependent kinase inhibitor 1A, hes family bHLH transcription factor 1, hes related family bHLH transcription factor with YRPW motif 1, MYC, NOTCH3, RE1 silencing transcription factor and transcription factor 7 in a cellular context-dependent manner, while non-canonical Notch signaling activates NF-κB and Rac family small GTPase 1. Notch signaling is aberrantly activated in breast cancer, non-small-cell lung cancer and hematological malignancies, such as T-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma. However, Notch signaling is inactivated in small-cell lung cancer and squamous cell carcinomas. Loss-of-function NOTCH1 mutations are early events during esophageal tumorigenesis, whereas gain-of-function NOTCH1 mutations are late events during T-cell leukemogenesis and B-cell lymphomagenesis. Notch signaling cascades crosstalk with fibroblast growth factor and WNT signaling cascades in the tumor microenvironment to maintain cancer stem cells and remodel the tumor microenvironment. The Notch signaling network exerts oncogenic and tumor-suppressive effects in a cancer stage-or (sub)type-dependent manner. Small-molecule γ-secretase inhibitors (AL101, MRK-560, nirogacestat and others) and antibody-based biologics targeting Notch ligands or receptors [ABT-165, AMG 119, rovalpituzumab tesirine (Rova-T) and others] have been developed as investigational drugs. The dLL3-targeting antibody-drug conjugate (Adc) Rova-T, and dLL3-targeting chimeric antigen receptor-modified T cells (CAR-Ts), AMG 119, are promising anti-cancer therapeutics, as are other Adcs or cARTs targeting tumor necrosis factor receptor superfamily member 17, cd19, cd22, cd30, cd79B, cd205, claudin 18.2, fibroblast growth factor receptor (FGFR)2, FGFR3, receptor-type tyrosine-protein kinase FLT3, HER2, hepatocyte growth factor receptor, NEcTIN4, inactive tyrosine-protein kinase 7, inactive tyrosine-protein kinase transmembrane receptor ROR1 and tumor-associated calcium signal transducer 2. Adcs and cARTs could alter the therapeutic framework for refractory cancers, especially diffuse-type gastric cancer, ovarian cancer and pancreatic cancer with peritoneal dissemination. Phase III clinical trials of Rova-T for patients with small-cell lung cancer and a phase III clinical trial of nirogacestat for patients with desmoid tumors are ongoing. Integration of human intelligence, cognitive computing and explainable artificial intelligence is necessary to construct a Notch-related knowledge-base and optimize Notch-targeted therapy for patients with cancer.

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Section: Therapeutics Targeting Notch Signaling Cascadesmentioning

confidence: 99%

Precision medicine for human cancers with Notch signaling dysregulation (Review)

Katoh¹,

2019

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“…The LALA-PG Fc variant was constructed as previously described (24). All fusion proteins were obtained via the FreeStyle 293 expression system (Invitrogen) according to previously reported methods (25,26) and subsequently purified using protein A-sepharose from the harvested cell culture supernatant. The purity of the fusion protein was determined by polyacrylamide gel electrophoresis.…”

Section: Fusion Proteinsmentioning

confidence: 99%

TIGIT-Fc Promote Immune Tolerance at the Feto-maternal Interface

Lei

et al. 2019

Preprint

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The perfect synchronization of maternal immune-endocrine mechanisms and those of the foetus is necessary for a successful pregnancy. In this report, decidual immune cells at the maternal-foetal interface were detected that expressed TIGIT (T cell immunoreceptor with Ig and ITIM domains), which is a co-inhibitory receptor that triggers immunological tolerance. We generated recombinant TIGIT-Fc fusion proteins by linking the extracellular domain of TIGIT and silent Fc fragments. The treatment with TIGIT-Fc of human decidual dendritic cells (dDCs) increased the production of interleukin 10 and induced the dDCs to powerfully polarize the decidual CD4 + T cells towards a classic T H 2 phenotype. The administration of TIGIT-Fc to CBA/J pregnant mice at preimplantation induced CD4 + forkhead box P3 + (Foxp3 + ) regulatory T cells and tolerogenic dendritic cells and increased pregnancy rates in a mouse model of abortive stress. Moreover, we proposed that progesterone play a direct role in the transcriptional regulation of the TIGIT gene in decidual immune cell subsets. The results suggested the therapeutic potential of the TIGIT-Fc fusion protein in reinstating immune tolerance in failing pregnancies. ~ 3 ~

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“…In HCC, CD44 is TIC marker most associated with the epithelial-mesenchymal transition (EMT), drug resistance and tumor formation in immunodeficient mice [9][10][11], suggesting that CD44 expression might be a crucial sign to guide clinical treatment. In addition, various stemness-related signals, such as Notch, Hippo, Wnt and Hedgehog signaling, are usually aberrantly activated in TICs, and drug resistance can be overcome by blocking these signals [12][13][14]. Among them, Hedgehog signaling, which is related to embryogenesis, participates in the differentiation of hepatocytes from endodermal progenitors [15].…”

Section: Introductionmentioning

confidence: 99%

Hedgehog signaling promotes sorafenib resistance in hepatocellular carcinoma patient-derived organoids

Wang

Xun

et al. 2020

J Exp Clin Cancer Res

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Background: The mechanism underlying sorafenib resistance in hepatocellular carcinoma (HCC) remains unclear. Accumulating evidence suggests that tumor-initiating cells (TICs) are a pivotal driving force. Both CD44 and Hedgehog signaling play crucial roles in TIC properties in HCC. In this study, we explored the roles of CD44 and Hedgehog signaling in sorafenib resistance and evaluated the therapeutic effect of cotreatment with sorafenib and Hedgehog signaling inhibitors in HCC patient-derived organoid (PDO) models to improve treatment efficacy. Methods: We collected HCC specimens to establish PDO models. Cell viability and malignant transformation properties were investigated after treatment with different TIC-related inhibitors alone or in combination with sorafenib to evaluate the therapeutic effect in PDOs and cell lines by in vitro and in vivo experiments. Expression levels of Hedgehog signaling proteins and CD44 were monitored to reveal potential relationships. Results: We demonstrated that our HCC PDO models strongly maintained the histological features of the corresponding tumors and responded to drug treatment. Furthermore, CD44-positive HCC PDOs were obviously resistant to sorafenib, and sorafenib increased CD44 levels. A drug screen showed that compared with Notch, Hippo and Wnt signaling inhibitors, a Hedgehog signaling inhibitor (GANT61) potently suppressed HCC PDO cell viability. In addition, there was a highly synergistic effect in vitro and in vivo on the suppression of cell viability and malignant properties when sorafenib and GANT61 were added to CD44-positive HCC PDOs and cell lines, respectively. Furthermore, the upregulation of CD44 and Hedgehog signaling induced by sorafenib was reversed by GANT61. Conclusions: GANT61 significantly suppressed Hedgehog signaling to reverse sorafenib resistance in CD44-positive HCC. The combination of sorafenib and Hedgehog signaling inhibitors might be effective in HCC patients with high CD44 levels as a personalized-medicine approach.

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Antagonism of EGFR and Notch limits resistance to EGFR inhibitors and radiation by decreasing tumor-initiating cell frequency

Cited by 62 publications

References 53 publications

Precision medicine for human cancers with Notch signaling dysregulation (Review)

Precision medicine for human cancers with Notch signaling dysregulation (Review)

TIGIT-Fc Promote Immune Tolerance at the Feto-maternal Interface

Hedgehog signaling promotes sorafenib resistance in hepatocellular carcinoma patient-derived organoids

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