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Identification of molecular targets for lung cancer metastasis and chemoresistance

  • 권옥선 (서강대학교 일반대학원)

초록/요약

종양의 이질성 (Heterogeneity)는 환자마다 항암제에 대한 상이한 반응성을 나타내는 원인으로 기존 항암치료의 한계점으로 대두되고 있다. 따라서 최근 종양 이질성의 한계를 극복하기 위해 환자 개인의 특성에 맞는 치료법을 제공하는 환자 맞춤형 치료법이 환자의 생존율을 높일 수 있는 유망한 치료전략으로 제시되고 있다. 최근 다양한 시퀀싱 기술의 발달로 인해 환자의 유전체 데이터 베이스가 확립되어 지고 있으며, 유전체 데이터를 기반한 표적 분자 발굴이 환자 맞춤형 치료의 효율을 높일 것으로 기대되고 있다. 이에, 본 연구에서 환자의 유전체 데이터 분석과 실험적 검증을 통해, GALNT14 유전자가 폐암 환자의 재발과 상관관계가 있으며 특히 폐암의 전이를 촉진시킴을 검증하였다. 하지만 GALNT14을 표적으로 하는 약물 개발의 어려움을 고려하여, 이를 극복하고자 두가지 대안을 제시하였다. 1) GALNT14에 의해 조절되는 하위 신호전달기전 억제 2) 약물 전사체 데이터 (Connectivity Map Approach)를 활용한 전이 억제 약물 발굴. 이를 통해 GALNT14에 의해 촉진된 전이를 억제할 수 있는 약물을 제안하였다. 또한, 본 연구를 통해 재발의 원인이 되는 중간엽 종양세포의 항암제 내성 획득 기전을 검증하였다. 더 나아가 BCL2에 의한 항암제 내성 획득 기전을 규명함으로서, 현재 임상적으로 적용 가능한 BCL2 억제제 (Navitoclax)를 항암제 내성을 극복하는 치료 전략을 제안하였다. 종합적으로 폐암의 재발의 주원인으로 작용하는 종양의 전이와 약물 저항성 획득의 분자 기전 연구를 기반으로, 종양의 재발의 표적 분자 발굴 및 그에 맞는 약물을 제공하여 폐암환자에게 적용 가능한 치료법을 제안함으로서 환자의 생존율을 높이는 이론적 토대 제공을 목표로 하였다.

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초록/요약

Despite enormous effort to developing and applying diverse therapeutic approach for targeting metastasis to cancer patients, metastasis is still remained as a main cause of cancer-related death in lung cancer. With recent advance in sequencing technology, tailor made therapy for each patient based on patient specific clinical feature has been considered as a promising therapeutic strategies for improving outcome for cancer patient. In this line, to stratify patients based on biomarker, identification of clinically relevant biomarker with paired drug is essential to design companion diagnosis. In this research, I aimed to identify the clinically relevant biomarker with paired therapeutic drugs of lung cancer metastasis with underlying molecular mechanism for providing biological background for designing companion diagnosis. Herein, I demonstrated that N-acetylgalactosaminyltransferase 14 (GALNT14), highly expressed in recurrence lung cancer, was inversely correlated with recurrence free survival in those with lung cancer. Of interest, the augmented metastatic potential resulted from enhanced WNT signaling with nuclear retention of -catenin protein, which led to HOXB9 expression. Given that GALNT14 and HOXB9 was strongly correlated with reduced recurrence-free survival and increased hazard risk, suggesting that targeting GALNT14/WNT/HOXB9 axis would be putative therapeutic approach to inhibit metastasis. However, due to poor druggability, developing drug for targeting GALNT14 and HOXB9 still remained as a challenging in drug development. In this line, I took advantage of Connectivity Map Approach (CMap) to predict a putative drug, of which effect could mimic to gene expression of loss of GALNT14, in drug repositioning (DR) library. Using system-based approach, I identified that Bortezomib (BTZ) exhibited inhibitory effect on metastasis with reversed metastasis related gene signature with similarity to depletion of GALNT14. Furthermore, I demonstrated that the inhibitory effect of BTZ resulted from modulating TGF signaling regardless of proteasome inhibition. In conclusion, BTZ would be a feasible therapeutic approach to inhibit metastasis potential of lung cancer patients with high expression of GALNT14. Furthermore, epithelial-mesenchymal transition (EMT), which is one of the main process to acquire metastatic potential, was recently shown to obtain chemoresistance through expressing EMT specific transcription factor. Therefore, I identified BCL2, which is highly induced in mesenchymal type of lung cancer, as a predictor of poor prognosis in mesenchymal lung cancer patient and association with acquired chemoresistance. Moreover, BCL2 expression was induced by ERK1 activity through the MEK1/ERK1 scaffold protein MEK partner-1 (MP1). Thereby, this results suggest that targeting MEK1/MP1/ERK1/BCL2 axis, such as MEK1 or BCL2, with currently available drug is a currently feasible approach to improve clinical outcomes of mesenchymal lung cancer patients. Taken together, it is crucial for identifying clinically relevant biomarker and paired drug with underlying molecular mechanism to improve clinical outcome of recurrent lung cancer patients in the future.

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