Dataset Information

Anti-HDGF Antibody Targets EGFR Tyrosine Kinase Inhibitor-Tolerant Cells in NSCLC Patient-Derived Xenografts.

ABSTRACT: Constitutively active mutant EGFR is one of the major oncogenic drivers in non-small cell lung cancer (NSCLC). Targeted therapy using EGFR tyrosine kinase inhibitor (TKI) is a first-line option in patients that have metastatic or recurring disease. However, despite the high response rate to TKI, most patients have a partial response, and the disease eventually progresses in 10 to 19 months. It is believed that drug-tolerant cells that survive TKI exposure during the progression-free period facilitate the emergence of acquired resistance. Thus, targeting the drug-tolerant cells could improve the treatment of NSCLC with EGFR mutations. We demonstrated here that EGFR-mutant patient-derived xenograft tumors responded partially to osimertinib despite near-complete inhibition of EGFR activation. Signaling in AKT/mTOR and MAPK pathways could be reactivated shortly after initial inhibition. As a result, many tumor cells escaped drug killing and regained growth following about 35 days of continuous osimertinib dosing. However, when an antibody to hepatoma-derived growth factor (HDGF) was given concurrently with osimertinib, tumors showed complete or near-complete responses. There was significant prolongation of progression-free survival of tumor-bearing mice as well. IHC and Western blot analysis of tumors collected in the early stages of treatment suggest that increased suppression of the AKT/mTOR and MAPK pathways could be a mechanism that results in enhanced efficacy of osimertinib when it is combined with an anti-HDGF antibody.

Significance

These results suggest that HDGF could be critically involved in promoting tolerance to TKI in patient-derived xenografts of NSCLC tumors. Blocking HDGF signaling could be a potential means to enhance EGFR-targeted therapy of NSCLC that warrants further advanced preclinical and clinical studies.

SUBMITTER: Zhou CQ

PROVIDER: S-EPMC11370239 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Anti-HDGF Antibody Targets EGFR Tyrosine Kinase Inhibitor-Tolerant Cells in NSCLC Patient-Derived Xenografts.

Zhou Cindy Q CQ Li Ariel A Ri Kaoru K Sultan Ahmed S AS Ren Hening H

Cancer research communications 20240901 9

Constitutively active mutant EGFR is one of the major oncogenic drivers in non-small cell lung cancer (NSCLC). Targeted therapy using EGFR tyrosine kinase inhibitor (TKI) is a first-line option in patients that have metastatic or recurring disease. However, despite the high response rate to TKI, most patients have a partial response, and the disease eventually progresses in 10 to 19 months. It is believed that drug-tolerant cells that survive TKI exposure during the progression-free period facil ...[more]

PMID: 39041204

Similar Datasets

Project description:BackgroundThis study aimed to investigate the efficacy of immunotherapy, as monotherapy or in combination, comparing to chemotherapy with or without anti-angiogenesis for advanced non-small cell lung cancer (NSCLC) patients progressing to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs).MethodsWe retrospectively analyzed patients with advanced NSCLC harboring EGFR mutations who received immune checkpoint inhibitors (ICI) and/or chemotherapy after EGFR-TKIs failure at Shanghai Chest Hospital between Aug 2016 and Oct 2022. According to the subsequent immunotherapy regimen, the patients were assigned to ICI monotherapy (IM), IO plus anti-angiogenesis (IA), ICI plus chemotherapy (IC), ICI plus chemotherapy plus anti-angiogenesis (ICA). Eligible patients undergoing standard chemotherapy were assigned to chemotherapy plus anti-angiogenesis (CA) and chemotherapy alone (CM). Efficacy was evaluated according to the RECIST 1.1version, and calculated the objective response rate (ORR) and disease control rate (DCR). Survival curves were plotted using the Kaplan-Meier method, and the median progression-free survival (PFS) was calculated. Differences among survival curves of the six groups were assessed using the log-rank test.ResultsA total of 237 advanced NSCLC patients with EGFR mutations were included in this study. Of the 160 patients who received immunotherapy, 57 received ICI monotherapy, 27 received ICI plus anti-angiogenesis therapy, 43 received ICI plus chemotherapy, and 33 received ICI plus anti-angiogenesis plus chemotherapy. 77 patients received standard chemotherapy, of which 30 received chemotherapy plus anti-angiogenesis and 47 received chemotherapy alone. Patients in ICA group showed significant longer PFS than IM (7.2 vs 1.9 months, P=0.011), IA (7.2 vs 4.8 months, P=0.009) and CM group (7.2 vs 4.4 months, P=0.005). There was no significant difference in PFS between the ICA and IC (7.2 vs 5.6 months, P=0.104) or CA (7.2 vs 6.7 months, P=0.959) group. Meanwhile, the ICA group showed the highest ORR and DCR (36.4% and 90.9%) compared to the other five groups. The IC group had a higher ORR than the IA and CA group (32.6% vs 7.4% vs 10.0%, respectively), but the DCR was comparable (79.1% vs 74.1% vs 76.7%, respectively). The ORR of the CM group was 6.4% and the DCR was 66.0%. IM group showed the lowest ORR and DCR (1.8% and 36.8%). Treatment-related adverse events (TRAEs) of grade 3 or worse occurred in 9 (27.3%) patients in the ICA group, 6 (20.0%) in the CA group, 7 (14.9%) in the CM group, 5 (11.6%) in the IC group, 5 (8.8%) in the IM group, and 2 (7.4%) in the IA group.ConclusionNSCLC patients with positive EGFR mutations after EGFR-TKIs failure received subsequent immunotherapy plus anti-angiogenesis and chemotherapy are likely to have more benefits in ORR, DCR and mPFS.

Dataset Information

Anti-HDGF Antibody Targets EGFR Tyrosine Kinase Inhibitor-Tolerant Cells in NSCLC Patient-Derived Xenografts.

Significance

Publications

Anti-HDGF Antibody Targets EGFR Tyrosine Kinase Inhibitor-Tolerant Cells in NSCLC Patient-Derived Xenografts.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets