PO.ET09.01 · 实验与分子治疗
KAT6i prifetrastat与PI3K通路抑制剂联用在PIK3CA突变型ER+乳腺癌临床前模型中驱动更优疗效
KAT6i prifetrastat combines with PI3K pathway inhibitors to drive superior efficacy in preclinical models of PIK3CA mutated ER+ BC
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
KAT6A及其旁系同源物KAT6B是组蛋白赖氨酸乙酰转移酶（HAT），可乙酰化组蛋白H3K23并调控谱系特异性转录程序。KAT6A/B活性在癌症中失调，导致KAT6A/B在包括乳腺癌在内的多种肿瘤类型中发挥致癌功能。Prifetrastat是一种首创的KAT6A和KAT6B催化抑制剂，相对其他HAT酶具有选择性。抑制KAT6A/B可下调包括雌激素信号、细胞周期和MYC在内的关键通路，从而在ER+乳腺癌中产生抗肿瘤活性。在此，我们评估了prifetrastat在涵盖不同亚型的一组乳腺癌细胞系中的活性。Prifetrastat应答在ER+、luminal亚群乳腺癌细胞系中富集，且在PIK3CA突变型和野生型（WT）细胞中均观察到活性。转录组学和染色质可及性分析表明，KAT6i处理在PIK3CA WT和突变型细胞系中抑制相似的通路。体内PDX研究也证实了prifetrastat在PIK3CA突变型模型中的疗效。鉴于KAT6i与PI3Kalpha抑制作用机制之间在ER+乳腺癌中的潜在相互作用，我们探索了prifetrastat与PI3Kalpha抑制剂联用的潜力。体外药物联合研究表明，在携带PIK3CA螺旋结构域或激酶结构域突变的细胞系中，prifetrastat与多种PI3Kalpha抑制剂（包括alpelisib和inavolisib，以及诸如tersolisib等突变选择性PI3Kalpha抑制剂）之间存在协同作用。机制上，与单药活性相比，prifetrastat与PI3Kalpha抑制剂联用可进一步抑制ER通路基因和细胞周期通路。最后，prifetrastat + 氟维司群（Fulvesterant）与PI3Kalpha抑制剂的三联组合在体内PIK3CA突变型ER+ PDX模型中驱动更深度的肿瘤生长抑制。总体而言，我们发现KAT6A/B抑制剂可有效地与PI3Kalpha抑制剂和内分泌治疗联用，以进一步提升在PIK3CA突变型ER+乳腺癌中的疗效，表明该三联组合可能为这一人群提供有前景的治疗选择。
查看英文原文 English abstract
KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HATs) that acetylate histone H3K23 and regulate lineage-specific transcriptional programs. KAT6A/B activity is dysregulated in cancer, resulting in an oncogenic function for KAT6A/B in several tumor types, including in breast cancer. Prifetrastat is a first in class catalytic inhibitor of KAT6A and KAT6B with selectivity over other HAT enzymes. KAT6A/B inhibition results in downregulation of key pathways including estrogen signaling, cell cycle and MYC, resulting in anti-tumor activity in ER+ breast cancer. Here, we evaluate the activity of prifetrastat across a panel of breast cancer cell lines comprising different subtypes. Prifetrastat response was enriched in ER+, luminal subset of breast cancer cell lines with activity observed in both PIK3CA mutant and WT cells. Transcriptomic and chromatin accessibility analyses demonstrate that KAT6i treatment inhibits similar pathways in both PIK3CA WT and mutant cell lines. In vivo PDX studies also confirm the efficacy of prifetrastat in PIK3CA mutated models. Given the potential interplay between the mechanisms of action of KAT6i and PI3Kalpha inhibition in ER+ BC, we explored the potential of combining prifetrastat with PI3Kalpha inhibitors. In vitro drug combination studies demonstrate synergy between prifetrastat and several PI3Kalpha inhibitors including alpelisib and inavolisib as well as mutant selective PI3Kalpha inhibitors such as tersolisib across cell lines harboring PIK3CA helical or kinase domain mutations. Mechanistically, the combination of prifetrastat with PI3Kalpha inhibitors leads to further suppression of ER pathway genes and cell cycle pathways as compared to monotherapy activity. Finally, the triple combination of prifetrastat + Fulvesterant with PI3Kalpha inhibitors drives deeper tumor growth inhibition in PIK3CA mutant ER+ PDX models in vivo. Overall, we find that KAT6A/B inhibitors can effectively be combined with PI3Kalpha inhibitors and endocrine therapy to further drive efficacy in PIK3CA-mutant ER+BC indicating that the triplet combination could present a promising therapeutic option for this population.
利益披露 Disclosure
K. P. Bhat,
Pfizer Employment.
J. Q. Cao,
Pfizer Employment.
C. B. Proffitt,
Pfizer Employment.
J. Petrovic,
Pfizer Employment.
X. Mu,
Pfizer Employment.
K. Spinler,
Pfizer Employment.
C. A. Flaveny,
Pfizer Employment.
T. A. Paul,
Pfizer Employment.
J. G. Mayor,
Pfizer Employment.
H. Neumann,
Pfizer Employment.
S. Sharma,
Pfizer Employment.