Abstract 430: Novel biomarkers for VEGFR inhibitors in metastatic renal cell carcinoma: BIM expression, and germline polymorphisms of BIM and PIK3R1
Authors: Kim Jee Hung , Kwon Woo Sun , Lee Won Suk , Kim Tae Soo , Park Kyu Hyun , Roh Jae Kyung , Ahn Joong Bae , Chung Hyun Cheol , Rha Sun Young 
Published: July 2016

Molecular targeted therapy, especially VEGFR tyrosine-kinase inhibitors (TKIs) including sunitinib, pazopanib and sorafenib has been the most efficacious therapy for metastatic renal cell carcinoma (mRCC). However, approximately 35% of mRCC patients do not get the benefit from TKIs treatment, due to resistance and/or drug induced toxicities.

Pro-apoptotic Bcl-2 family member (BIM) is a particularly critical mediator of targeted therapy-induced apoptosis in solid tumors. In previous, it had known that TKIs induced to BIM upregulation and then accelerated to apoptosis of tumor. However, according to recent several studies, BIM germline deletion polymorphism was identified as one of the primary resistant mechanisms of various TKIs in EGFR mutated NSCLC or CML. In addition, the alteration of phosphoinositide 3 kinase(PIK3)/protein kinase B(AKT) pathway has also been found as important mechanism in various cancer cell growth, proliferation and survival. PI3KR1 encodes the p85α subunit, regulatory subunits of Class IA PIK3s. Germline PIK3R1 variant M326I(c.978G&gt;A) might affect the sensitivity of receptor tyrosine kinase (RTK) inhibitors and its downstream pathway inhibitors.

We evaluated the possibility of BIM, PIK3R1 as a potential biomarker for VEGFR TKIs in mRCC. BIM deletion polymorphism status of gDNA from formalin fixed paraffin embedded (FFPE) tumor tissues and peripheral blood mononucleated cells (PBMC) of mRCC patients was determined by separated PCR. And we evaluated BIM protein expression by immunohistochemistry. We also evaluated PIK3R1 germline mutation by pyrosequencing in PBMC of mRCC patients.Germline BIM deletion accounted for 17.8% of total 124 mRCC patients. Unlike with previous other studies, our data suggested that BIM wild type showed tendency to poor prognosis with sunitinib or sorafenib treatments for clear cell type RCC (median OS of BIM wild and deleted type: 44.9 vs 67.3 months, p = 0.279), and high expression of BIM (median OS of BIM low(&lt;10%), median(10-50%) and high(&gt;50%) respectively: 76.5 vs 60.0 vs 21.3 months, p = 0.005). In addition, we found 26% (19/71) of the germline PIK3R1 variant in mRCC. Patients with PIK3R1 germline variant showed a tendency of poor prognosis to 1st line VEGFR TKI treatment than wild type (median PFS: 7.78 vs 15.87months, p = 0.342). Especially PFS of 1st line sunitinib treatment was significantly shorter in PIK3R1 variant compared to wild type (median PFS 7.78 vs 16.33 months, p = 0.004). But, there is no difference in mTOR inhibitor sensitivity both with PIK3R1 or BIM polymorphism.In conclusion, BIM expression and germline variants of BIM and PIK3R1 might be candidate biomarkers for VEGFR TKIs in mRCC.

Citation Format: Jee Hung Kim, Woo Sun Kwon, Won Suk Lee, Tae Soo Kim, Kyu Hyun Park, Jae Kyung Roh, Joong Bae Ahn, Hyun Cheol Chung, Sun Young Rha. Novel biomarkers for VEGFR inhibitors in metastatic renal cell carcinoma: BIM expression, and germline polymorphisms of BIM and PIK3R1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 430.