PO.CL07.02 · 临床研究

PIK3CA与ARID1A共改变的肿瘤对AKT抑制剂capivasertib敏感

PIK3CA and ARID1A co-altered tumors are sensitive to AKT inhibitor, capivasertib

编号 3920 展板 26 时间 4/20 02:00–05:00 区域 Section 47 主讲 Rian Engeldinger, No Degree

分会场 Molecular Targeted Therapy

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作者与单位 Authors & Affiliations

Rian Engeldinger¹, Shirsa Udgata¹, Jordan Noelle Stoecker¹, Xingqi Shen¹, Ruchi Shah¹, Alexa Schmitz¹, Katherine A. Johnson¹, Cheri Pasch¹, Dustin A. Deming²

¹Univ. of Wisconsin Madison Sch. of Med. & Public Health, Madison, WI,²University of Wisconsin Carbone Cancer Center, Madison, WI

摘要 Abstract

中文摘要

背景：PIK3CA（PK）与ARID1A（AD）共改变发生于1%的癌症中。在MATCH试验的Z1F臂中，这些癌症对copanlisib（cop）的PI3K抑制具有增强的敏感性。鉴于AKT抑制剂capivasertib（capi）近期获FDA批准，我们在此旨在评估capi治疗在PK和AD改变背景下的潜在获益，以及可能发生敏感性增强的机制。方法：采用CRISPR/Cas9从SW48PIK3CA-H1047R（SW48PK）以及PIK3CAH1047R突变型局部晚期直肠癌（LARC）患者来源癌症类器官（PDCO）中敲除AD。从NCI资源库获得PK或PKAD的结直肠癌（CRC）、卵巢癌（OC）和肾癌（RC）PDCO，并用2 μM capi处理48小时。在处理前后（capi或对照）测量最长直径的相对变化百分比（PRC），并使用Glass's delta（GD）测量效应量。采用Western blot测定PI3K蛋白（RPS6、AKT）、凋亡蛋白（MCL-1、BCL-xL、Bax、Bims）以及mTORC1蛋白PRAS40的水平。将SW48PK和SW48PKAD注射至无胸腺裸鼠胁部，以100mg/kg capi（10% DMSO溶于90%的20% SBE-beta-CD生理盐水中）或载体每日两次（b.i.d）处理28天或直至濒死。通过免疫组化（IHC）评估这些肿瘤中的Ki-67和cleaved caspase-3，并量化为阳性细胞数/高倍视野（HPF）。结果：在PKAD共改变的CRC PK（PRC 4.8%，GD 2.0）、LARC-PK（0.5%，0.9）、OC-PKAD（10%，1.03）、RC-PKAD（1.52%，1.52）和LARC-PKAD（2.91%，1.78）PDCO中均观察到capi的治疗反应，表明在各癌种中均有敏感性，且在LARC中共改变细胞系相对于单纯PK具有增强的敏感性。Western blot显示，与LARC-PK相比，LARC-PKAD在6小时时p-RPS6的降低更明显，但在2D细胞系中未见显著差异。capi处理后，所有2D和3D细胞系中p-AKT均升高。在凋亡蛋白中，BCL-xL在共突变培养物中随时间稳定升高。与LARC-PK相比，Bims（Bim的细胞毒性亚型）在LARC-PKAD中6小时时诱导更强。p-PRAS40、MCL-1、Bax和Bak的水平在各细胞系间大体相当。在体内，PKAD肿瘤经capi治疗后显示出显著的肿瘤生长延迟（p = 0.01），而PK肿瘤则没有（p = 0.06）。结论：相对于PIK3CA突变型肿瘤，PIK3CA与ARID1A共改变的肿瘤对capi具有增强的敏感性，可能通过诱导Bims实现。应在PIK3CA与ARID1A共改变的癌症中进一步开展capi的临床研究。此外，有必要进一步开展研究以确定与capi联用的新型药物组合，从而进一步增强患者的反应。

查看英文原文 English abstract

Background: PIK3CA (PK) and ARID1A (AD) co-alterations occur in 1% of cancers. These cancers had enhanced sensitivity to PI3K inhibition with copanlisib (cop) in the MATCH trial arm Z1F. Given the recent FDA approval of the AKT inhibitor, capivasertib (capi), here we aim to evaluate the potential benefit of capi treatment in the setting of PK and AD alterations and the mechanism by which enhanced sensitivity might be occurring. Methods: CRISPR/Cas9 was used to knockout AD from SW48PIK3CA-H1047R (SW48PK), and PIK3CAH1047R mutant locally advanced rectal cancer (LARC) patient-derived cancer organoids (PDCOs). PK or PKAD Colorectal (CRC), ovarian (OC), and renal (RC)PDCOs were obtained from the NCI repository and were treated with 2 µM capi for 48 hrs. Percent relative change in the longest diameter (PRC) was measured prior to and after treatment in(capi or control) and effect size was measured using Glass's delta (GD) . Western blot was used to determine levels of PI3K proteins (RPS6, AKT), apoptotic proteins (MCL-1, BCL-xL, Bax, Bims), and mTORC1 protein, PRAS40. Athymic nude mice were flank injected with SW48PK and SW48PKAD and treated with 100mg/kg capi (10% DMSO in 90% of 20% SBE-beta-CD in saline) or vehicle b.i.d for 28 days or until moribund. Ki-67 and cleaved caspase-3 in these tumors were assessed by immunohistochemistry (IHC) and quantified as positive cells/high powered field (HPF). Results: Capi treatment responses were observed in PKAD co-altered CRC PK (PRC 4.8%, GD 2.0), LARC-PK (0.5%, 0.9), OC-PKAD(10%, 1.03), RC-PKAD (1.52%, 1.52), and LARC-PKAD (2.91%, 1.78) PDCOs, indicating sensitivity across cancer types and enhanced sensitivity in co-altered lines relative to PK alone for LARC. Western blot showed greater reduction in p-RPS6 in LARC-PKAD by 6h compared to LARC-PK, but no significant differences were seen in 2D lines. p-AKT increased upon capi treatment across all 2D and 3D lines. Among apoptotic proteins, BCL-xL steadily increased over time in co-mutant cultures. Bims (cytotoxic isoform of Bim) had a stronger induction in 6h in LARC-PKAD compared to LARC-PK. Levels of p-PRAS40, MCL-1, Bax, and Bak remained largely comparable across lines. In vivo, PKAD tumors showed a significant tumor growth delay (p = 0.01) with capi treatment, while PK tumors did not (p = 0.06). Conclusion: PIK3CA and ARID1A co-altered tumors have enhanced sensitivity to capi relative to PIK3CA mutant tumors, potentially through induction of Bims. Capi should be investigated further clinically in PIK3CA and ARID1A co-altered cancers. Additionally, further studies identifying novel drug combinations with capi are warranted to further enhance patient response

利益披露 Disclosure

R. Engeldinger, None.. S. Udgata, None.. J. N. Stoecker, None.. X. Shen, None.. R. Shah, None.. A. Schmitz, None.. K. A. Johnson, None.. C. Pasch, None. D. A. Deming, Merck Other, Research Funding. Genentech Other, Research Funding. Bristol Myers Squibb Other, Research Funding, Consulting/Advisory Boards. Pfizer Other, Research Funding, Consulting/Advisory Boards. Promega Other, Research Funding. Arcus Other, Research Funding. Ipsen Other, Research Funding. Eli Lilly Other, Research Funding, Consulting/Advisory Boards. Transthera Other, Research Funding. ImmutoScientific Other, Research Funding. Foundation Medicine Other, Consulting/Advisory Boards. Illumina Other, Consulting/Advisory Boards. Regeneron Other, Consulting/Advisory Boards. Aadi Biosciences Other, Consulting/Advisory Boards. Taiho Other, Consulting/Advisory Boards. Inocras Other, Consulting/Advisory Boards. DoMoreDx Other, Consulting/Advisory Boards. Fortvita Other, Consulting/Advisory Boards. Exelixis Other, Consulting/Advisory Boards. Takeda Other, Consulting/Advisory Boards.

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