Abstract 1911: A common BIM polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer

Autor: Yao Fei, Axel M. Hillmer, Yeow Tee Goh, Shenli Zhang, John Carson Allen, Pramila N. Ariyaratne, Kazutoshi Isobe, King Pan Ng, Markus M. Nöthen, Charles Chuah, Wah Heng Lee, Hiroyuki Mano, V. S. Nadarajan, Yijun Ruan, Eng Huat Tan, Vikrant Kumar, Niranjan Nagarajan, Noan-Minh Chau, Xiaoan Ruan, Atif Shahab, Manabu Soda, Yasushi Yatabe, S. Tiong Ong, Mei-Kim Ang, Wing-Kin Sung, Daniel Shao-Weng Tan, Wee Joo Chng, Dianne Poh, John W.J. Huang, Audrey S.M. Teo, Sheila Soh, Xing Yi Woo, Tien Yin Wong, Patrick Tan, Tan Min Chin, Kenichi Sawada, Tun-Kiat Ko, Lay Cheng Lim, Liang Piu Koh, Wan Ting Poh, Ross A. Soo, Ju Ee Seet, Wan-Teck Lim, Hein Than, Quan Sing Ng, Wen Chun Juan, L.Y. Yang, Naoto Takahashi, Anbupalam Thalamuthu, Valere Cacheux-Rataboul
Rok vydání: 2012
Předmět:
Zdroj: Cancer Research. 72:1911-1911
ISSN: 1538-7445
0008-5472
DOI: 10.1158/1538-7445.am2012-1911
Popis: The use of tyrosine kinase inhibitors (TKI) to target oncogenic kinases has led to remarkable responses in patients with chronic myeloid leukemia (CML) and EGFR-mutated non-small cell lung cancer (EGFR NSCLC). However, a significant subset of patients have a minimal or very brief response. It has been suggested that germline polymorphisms may account for this upfront TKI resistance, and that identifying such polymorphisms will allow personalization of targeted therapy to achieve optimal responses in patients. Using paired-end DNA sequencing, we discovered a common (12.3% carrier rate) deletion polymorphism in intron 2 of the BIM gene. BIM is a pro-apoptotic member of the BCL2 family of proteins, and is required for TKIs to induce apoptosis in many cancers. We investigated the effects of the polymorphism on BIM function and TKI resistance in CML and EGFR NSCLC. Inspection of BIM gene structure suggested the polymorphism would result in mutually exclusive splicing of exon 3 (E3) and 4 (E4). Importantly, such an event is predicted to affect TKI sensitivity, since the pro-apoptotic BH3 domain is found only in E4. Using minigenes, we confirmed the deletion favored splicing of E3 over E4 by 5-fold (p=0.008), and that the deletion contained a cis-acting splicing suppressor. Next, using Zn finger nuclease-editing, we recreated the polymorphism in TKI sensitive CML (K562) and EGFR NSCLC (PC9) cell lines. Polymorphism-containing subclones had increased E3/E4 transcript ratios, decreased expression of BH3-containing BIM protein and defective apoptotic signaling, and were intrinsically TKI resistant. Importantly, while manipulation of E3-containing transcript levels did not alter the resistance phenotype, pharmacologic restoration of BH3 function (using a BH3 mimetic ABT-737) restored apoptotic signaling as well as TKI-sensitivity. Finally, we determined if the polymorphism predicted for inferior clinical responses in TKI-treated CML and EGFR NSCLC patients. In 203 CML patients, the polymorphism predicted inferior imatinib responses (defined by EuropeanLeukemiaNet criteria) among those with the polymorphism vs those without (odds ratio=2.94, p=0.02, 95% CI 1.17-7.43). In 141 EGFR NSCLC patients, the polymorphism predicted a shorter PFS of 6.6 vs 11.9 months (p=0.0027), and was independently prognostic for poorer PFS (hazard ratio=2.14, p=0.0026, 95% CI 1.30-3.50). In summary, by altering BIM splicing, the BIM polymorphism is sufficient to cause intrinsic TKI resistance in vitro, and predicts inferior TKI responses in patients. Upfront testing of CML and EGFR NSCLC patients for the BIM polymorphism may identify individuals at risk for developing clinical TKI resistance. Our results also offer an explanation for the heterogeneity of TKI responses among CML and EGFR NSCLC patients, and suggest the possibility of personalizing therapy with BH3 mimetics to improve TKI responses. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1911. doi:1538-7445.AM2012-1911
Databáze: OpenAIRE
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