Evaluation of patritumab with or without erlotinib in combination with standard cytotoxic agents against pediatric sarcoma xenograft models

Bandyopadhyay, Abhik; Favours, Edward; Phelps, Doris A.; Pozo, Vanessa Del; Ghilu, Samson; Kurmashev, Dias; Michalek, Joel E.; Treviño, Arturo Zárate; Guttridge, Denis C.; London, Cheryl A.; Hirotani, Kenji; Zhang, Ling; Kurmasheva, Raushan T.; Houghton, Peter J.

doi:10.1002/pbc.26870

Cited by 10 publications

(9 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…When using VS-4718 in the µM range, only FAK and FLT3 have negligible activity with the latter expressed only in cells of hematopoietic origin [ 43 ]. The IC 50 of VS-4718 in pancreatic cancer cell lines ranged from 1.23 to 3.99 µM, whereby the response between the three cell lines to VS-4718 varied, which is in agreement with the findings of Shapiro et al., who reported fluctuations in IC 50 of VS-4718 in different cell lines, having attributed it to the difference in Merlin’s expression which regulates FAK function [ 44 ], and also with findings in pediatric tumor cell lines [ 45 ]. The pharmacological inhibition of FAK could be improved further, especially in the MIA PaCa 2 cell line if higher doses were used.…”

Section: Discussionsupporting

confidence: 87%

FAK inhibition radiosensitizes pancreatic ductal adenocarcinoma cells in vitro

et al. 2020

View full text Add to dashboard Cite

Introduction Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase protein frequently overexpressed in cancer and has been linked to an increase in the stem cell population of tumors, resistance to therapy, and metastatic spread. Pharmacological FAK inhibition in pancreatic cancer has received increased attention over the last few years, either alone or in combination with other therapeutics including chemotherapy and immunotherapy. However, its prognostic value and its role in radioresistance of pancreatic ducal adenocarcinoma (PDAC) is unknown. Methods and materials Using the TCGA and GTEx databases, we investigated the genetic alterations and mRNA expression levels of PTK2 (the encoding-gene for FAK) in normal pancreatic tissue and pancreatic cancer and its impact on patient survival. Furthermore, we evaluated the expression of FAK and its tyrosine domain Ty-397 in three pancreatic cancer cell lines. We went further and evaluated the role of a commercial FAK tyrosine kinase inhibitor VS-4718 on the viability and radiosensitization of the pancreatic cell lines as well as its effect on the extracellular matrix (ECM) production from the pancreatic stellate cells. Furthermore, we tested the effect of combining radiation with VS-4718 in a three-dimensional (3D) multicellular pancreatic tumor spheroid model. Results A database analysis revealed a relevant increase in genetic alterations and mRNA expression of the PTK2 in PDAC, which were associated with lower progression-free survival. In vitro, there was only variation in the basal phosphorylation level of FAK in cell lines. VS-4718 radiosensitized pancreatic cell lines only in the presence of ECM-producing pancreatic stellate cells and markedly reduced the ECM production in the stromal cells. Finally, using a 3D multicellular tumor model, the combination of VS-4718 and radiotherapy significantly reduced the growth of tumor aggregates. Conclusion Pharmacological inhibition of FAK in pancreatic cancer could be a novel therapeutic strategy as our results show a radiosensitization effect of VS-4718 in vitro in a multicellular 2D-and in a 3D-model of pancreatic cancer.

show abstract

Section: Discussionsupporting

confidence: 87%

FAK inhibition radiosensitizes pancreatic ductal adenocarcinoma cells in vitro

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Available therapies targeting EGFR include monoclonal antibodies, e.g. nimotuzumab and cetuximab [24, 25], and tyrosine kinase inhibitors such as erlotinib and gefitinib [26, 27]. However, most current therapies targeting EGFR in osteosarcoma patients have not fulfilled expectations in clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Sodium cantharidate targets STAT3 and abrogates EGFR inhibitor resistance in osteosarcoma

2019

Aging

View full text Add to dashboard Cite

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. Overactive EGFR signaling is frequently seen in osteosarcoma cells, and represents a potential therapeutic target. However, feedback activation of STAT3 after EGFR inhibition is linked to treatment resistance, suggesting that combined EGFR/STAT3 inhibition may be needed to overcome this effect. Cantharidin and its analogues have shown strong anticancer effects, including STAT3 inhibition, in several tumor cells. Therefore, we investigated the effects of sodium cantharidate (SC), either as monotherapy and in combination with the EGFR inhibitor erlotinib, on STAT3 activation and osteosarcoma cell growth. Cell viability, migration, and apoptosis assays were performed in human MG63 and U2OS cells, and MG63 xenografts were generated in nude mice to verify the suppression of tumor growth in vivo. Additionally, western blotting and immunohistochemistry were used to verify the STAT3 and EGFR phosphorylation statuses in xenografts. We found that SC repressed cell viability and migration and induced apoptosis in vitro, while combined SC and erlotinib treatment enhanced osteosarcoma growth suppression by preventing feedback activation of STAT3. These data support further development of cantharidin-based combination therapies for metastatic and recurrent/refractory osteosarcoma.

show abstract

“…HER3 is expressed by most RMS cell lines [ 67 ]. Some ARMS cell lines, showing an abundant expression level of HER3 and its phosphorylation, were chosen to test the efficacy of patritumab, an anti-HER3 monoclonal antibody, alone or in combination with erlotinib, an anti-EGFR inhibitor, or with standard cytotoxic agents.…”

Section: Her Family Members As Therapeutic Targetsmentioning

confidence: 99%

HER Tyrosine Kinase Family and Rhabdomyosarcoma: Role in Onset and Targeted Therapy

Giovanni

Landuzzi

Palladini

et al. 2021

Cells

View full text Add to dashboard Cite

Rhabdomyosarcomas (RMS) are tumors of the skeletal muscle lineage. Two main features allow for distinction between subtypes: morphology and presence/absence of a translocation between the PAX3 (or PAX7) and FOXO1 genes. The two main subtypes are fusion-positive alveolar RMS (ARMS) and fusion-negative embryonal RMS (ERMS). This review will focus on the role of receptor tyrosine kinases of the human epidermal growth factor receptor (EGFR) family that is comprised EGFR itself, HER2, HER3 and HER4 in RMS onset and the potential therapeutic targeting of receptor tyrosine kinases. EGFR is highly expressed by ERMS tumors and cell lines, in some cases contributing to tumor growth. If not mutated, HER2 is not directly involved in control of RMS cell growth but can be expressed at significant levels. A minority of ERMS carries a HER2 mutation with driving activity on tumor growth. HER3 is frequently overexpressed by RMS and can play a role in the residual myogenic differentiation ability and in resistance to signaling-directed therapy. HER family members could be exploited for therapeutic approaches in two ways: blocking the HER member (playing a driving role for tumor growth with antibodies or inhibitors) and targeting expressed HER members to vehiculate toxins or immune effectors.

show abstract

Evaluation of patritumab with or without erlotinib in combination with standard cytotoxic agents against pediatric sarcoma xenograft models

Abstract: P had no single-agent activity, although it marginally potentiated the activity of vincristine and cisplatin in one of three models studied. However, the addition of E necessitated dose reduction of each cytotoxic agent, abrogating the enhancement observed with P alone.

Cited by 10 publications

References 44 publications

FAK inhibition radiosensitizes pancreatic ductal adenocarcinoma cells in vitro

FAK inhibition radiosensitizes pancreatic ductal adenocarcinoma cells in vitro

Sodium cantharidate targets STAT3 and abrogates EGFR inhibitor resistance in osteosarcoma

HER Tyrosine Kinase Family and Rhabdomyosarcoma: Role in Onset and Targeted Therapy

Contact Info

Product

Resources

About