Abstract 2958: Drug induced resistant tumor models enable the development of next-generation anticancer therapeutics

Abstract

Abstract Recent advances in cancer biology and diagnosis are providing more targeted approaches to treat cancers. Therapy targeting the specific oncogenic driver could inhibit tumor progression and helps to a favorable prognosis in clinical practice. Recently, the discovery of driver mutations in various cancers such as EGFR, ER, CDK, c–MET, TRK and BTK provides a personalized targeted treatment. However, most patients who initially benefit a lot from targeted therapies eventually become resistant to treatments. Acquired resistance limits the long–term efficacy. The commonly acquired resistant mechanisms include target gene mutation, alternative pathway activation, histological or phenotypic transformation and so on. Although a variety of mechanisms of acquired resistance have been reported, optimal treatment for acquired resistance is not yet clearly defined. To mimic the clinical resistant after long–term treatment, we established a panel of in vivo induced drug resistant CDX and PDX models by continuous dosing of targeted drugs to mice, covering a series of first–line targeted drugs Tamoxifen, Olaparib, BMN–673, Ibrutinib, Crizotinib, Erlotinib, Palbociclib, Capmatinib, Entrectinib, Cabozantinib, Sorafenib and Irinotecan. Resistant models were derived from sensitive models harboring specific oncogenic driver. Regrowth tumors were continually treated with targeted drugs and passaged several times until a stable drug resistance phenotype occurred. To explore the resistant mechanisms, we performed WES and RNA–seq analysis in the gene expression levels, and western blotting and IHC staining in the protein expression levels. In summary, these drug induced resistant tumor models provide an opportunity to evaluate the next–generation anticancer therapeutics to overcome therapeutic resistance in tumors. Citation Format: Ting Ni, Zhixiang Zhang, Xuzhen Tang, Wenting Shi, Qingyang Gu, Qunsheng Ji. Drug induced resistant tumor models enable the development of next-generation anticancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2958.