Abstract 1316: Preclinical evaluation of TUL-001, an EGFR inhibitor for the treatment of NSCLC with brain metastasis (BM)
Authors: Liu Xile , Mu Liwei , Liu Bin , Wu Shouting , Wang Degang , Zhang Lu , Ding Charles Z , Hu Lihong , Mao Weifeng , Zhu Zhenzhen , Chen Chen , Xia Yuanfeng , Chan Chichung , Chen Shuhui 
Published: August 2019

Abstract
Objective: Non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor-activating mutations (EGFRm+) have a much higher risk of developing CNS metastases. The cumulative incidence of BM and LM in these patients is more than 50%. These patients have poor prognosis as there are no approved drugs for these indications. Currently approved drugs can neither effectively treat brain metastases nor prevent development of the brain metastases due to their limited blood-brain-barrier (BBB) penetration. TUL-001 is a potent oral EGFR inhibitor, which has excellent potency and BBB (blood brain barrier) penetration ability, it can potently induces tumor regression both in the brain metastases and subcutaneous animal models.
Methods: The anti-proliferative activity of TUL-001 was evaluated in PC-9 (EGFRExon19 Del), and A431 (EGFRWT) NSCLC cell lines. The anti-tumor activity was evaluated in PC-9-luc Lung cancer brain metastases model, which was monitored by an IVIS Xenogen imaging system. The in vivo anti-tumor activity also evaluated in PC-9 subcutaneous transplantation tumor model. Effects on EGFR signaling pathway were assessed by western blot analysis of the downstream effector proteins p-EGFR (Y1068), p-AKT (Ser473) and p-ERK (Thr202/Tyr204).
Results: TUL-001 displayed potent anti-proliferative activity in the EGFR mutant cell line PC-9 (IC50 =3.74 nM), and less potent activity in the A431 (EGFRWT) cell line (IC50 = 54.1 nM), it has about 14 fold selectivity for EGFRExon19 Del over EGFRWT. TUL-001 significantly inhibited tumor growth at all doses tested in the PC-9-luc brain metastases model, and significantly prolong the overall survival for the test animals. In the PC-9 subcutaneous transplantation tumor model, TUL-001 can also shrinkage the tumors, and the TGI for the lower dose group (2.5mpk) was more than 120%. Western blot analysis of the tumor samples in the brain metastases model study showed that TUL-001 inhibited p-EGFR (Y1068), p-AKT (Ser473), and p-ERK (Thr202/Tyr204), indicating that the tumor growth inhibition was through inhibition of the resistant mutant EGFR.
Conclusion: TUL-001 is a potent brain penetrant EGFR inhibitor, and showed excellent antitumor activity in preclinical tumor models. These results warrant TUL-001 going to the clinic study for exploration of its potential for treating EGFRm+ NSCLC cancer with and without brain metastasis.
Citation Format: Xile Liu, Liwei Mu, Bin Liu, Shouting Wu, Degang Wang, Lu Zhang, Charles Z Ding, Lihong Hu, Weifeng Mao, Zhenzhen Zhu, Chen Chen, Yuanfeng Xia, Chichung Chan, Shuhui Chen. Preclinical evaluation of TUL-001, an EGFR inhibitor for the treatment of NSCLC with brain metastasis (BM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1316.