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A Phase 1/2 Trial of Ruxolitinib and Erlotinib in Patients with EGFR-Mutant Lung Adenocarcinomas with Acquired Resistance to Erlotinib.

ABSTRACT: Resistance to EGFR tyrosine kinase inhibitors develops in patients with EGFR-mutant lung cancers. New treatments are needed to address resistance not mediated by EGFR T790M; preclinical evidence suggests that the Janus kinase/signal transducers and activators of transcription signaling pathway is important in acquired resistance to EGFR-directed therapy.We evaluated the toxicity and efficacy of erlotinib and ruxolitinib in patients with EGFR-mutant lung cancers with acquired resistance to erlotinib. Exosomes were analyzed to assess changes in relevant protein expression during treatment.We enrolled 22 patients: 12 patients in the phase 1 portion of the study and 10 patients in the phase 2 portion. We did not observe any dose-limiting toxicities. The maximum tolerated dose of erlotinib was 150 mg daily and that of ruxolitinib was 20 mg twice daily. The most frequent toxicities (any grade) were anemia, diarrhea, and elevation of liver function test results. One partial response was observed (5% [95% confidence interval: 0-13]). The median progression-free survival was 2.2 months (95% confidence interval: 1.4-4.1).This is the first study assessing the combination of EGFR and Janus kinase inhibition in patients with EGFR-mutant lung cancers. The combination was well tolerated but ineffective. Exosomal EGFR levels may reflect changes in tumor EGFR expression in response to therapy.

SUBMITTER: Yu HA

PROVIDER: S-EPMC5552054 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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A Phase 1/2 Trial of Ruxolitinib and Erlotinib in Patients with EGFR-Mutant Lung Adenocarcinomas with Acquired Resistance to Erlotinib.

Yu Helena A HA Perez Leslie L Chang Qing Q Gao Sizhi P SP Kris Mark G MG Riely Gregory J GJ Bromberg Jacqueline J

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 20160906 1

<h4>Introduction</h4>Resistance to EGFR tyrosine kinase inhibitors develops in patients with EGFR-mutant lung cancers. New treatments are needed to address resistance not mediated by EGFR T790M; preclinical evidence suggests that the Janus kinase/signal transducers and activators of transcription signaling pathway is important in acquired resistance to EGFR-directed therapy.<h4>Methods</h4>We evaluated the toxicity and efficacy of erlotinib and ruxolitinib in patients with EGFR-mutant lung cance ...[more]

PMID: 27613527

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Project description:How to improve the efficacy and reverse the resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as erlotinib, remains a major challenge in the targeted therapy of lung adenocarcinoma with EGFR-activating mutation. Phosphoglycerate dehydrogenase (PHGDH) is the key enzyme of de novo serine biosynthesis over-expressed in various types of cancer including lung cancer. Elevated PHGDH expression is correlated with a worse overall survival in clinical lung adenocarcinoma patients. Here we investigated the role of PHGDH in lung adenocarcinoma with the acquisition of resistance to erlotinib. Methods: The necessary genes required for the acquired erlotinib resistance in lung adenocarcinoma cells were screened out by RNA-Seq analysis. Then the protein and mRNA levels of PHGDH were confirmed by immunoblotting and qRT-PCR in the erlotinib resistant cells. The effects of PHGDH inhibition or overexpression on erlotinib resistance were examined using cell culture and tumor xenograft mouse models respectively. To explore mechanism, the ROS level and DNA damage marker, ?H2AX, were tested by DCFH-DA staining and immunofluorescence after PHGDH inhibition. Results: We found that PHGDH level was significantly increased in the lung adenocarcinoma PC9ER4 and HCC827ER9 cells that acquired resistance to erlotinib. Perturbation of PHGDH by siPHGDH transfection or NCT-503, a small molecular PHGDH inhibitor, synergistically augmented the tumoricidal effect and restored sensitivity to erlotinib in cell lines and xenografts. Over-expression of PHGDH caused xenografts resistant to erlotinib. Furthermore, multiple DNA damage repair pathways related genes were changed by PHGDH depletion specifically in erlotinib resistant cells. ROS stress and DNA damage marker ?H2AX were enhanced by siPHGDH and NCT-503, which was reversed by NAC. Conclusion: Our study indicated that PHGDH inhibition has potential therapeutic value in lung adenocarcinoma with the acquired resistance to EGFR-TKIs.

Dataset Information

A Phase 1/2 Trial of Ruxolitinib and Erlotinib in Patients with EGFR-Mutant Lung Adenocarcinomas with Acquired Resistance to Erlotinib.

Publications

A Phase 1/2 Trial of Ruxolitinib and Erlotinib in Patients with EGFR-Mutant Lung Adenocarcinomas with Acquired Resistance to Erlotinib.

Similar Datasets

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