KRAS-enhanced macropinocytosis and reduced FcRn-mediated recycling sensitize pancreatic cancer to albumin-conjugated drugs

Pancreatic ductal adenocarcinoma (PDAC) is a dominantly (similar to 95%) KRAS-mutant cancer that has extremely poor prognosis, in part this is due to its strong intrinsic resistance towards almost all therapeutic agents. PDAC relies heavily on KRAS-transformed metabolism, including enhanced macropinocytosis and catabolism of extracellular albumin, to maintain its proliferation and progression. However, it has yet to be validated that whether such transformed metabolism could be exploited for the drug delivery to open therapeutic windows of cytotoxic agents in KRAS-mutant PDAC. In this study, we attempt to answer this question by focusing on the impact of two critical regulators of albumin catabolism, KRAS and the neonatal Fc receptor (FcRn), on the sensitivity of PDAC to doxorubicin (DOX, a model cytotoxic agent) and albumin-conjugated doxorubicin (DOX-ALB). Using cell lines and cell-derived xenografts with different KRAS genotypes and FcRn levels, we demonstrated that KRAS-enhanced macropinocytosis and reduced FcRn expression sensitize PDAC to DOX-ALB but not free DOX. In both in vitro and in vivo comparsion, the DOX-ALB demonstrated similar to 10 times enlarged therapeutic window compared with free DOX, in PDAC with KRAS mutation and reduced FcRn level, two events appear to occur simultaneously in the investigated PDAC. In summary, we conclude that albumin conjugation is an exploitable drug delivery strategy that significantly opens the therapeutic windows of otherwise undevelopable anti-cancer agents for KRAS-mutant PDAC therapy, and creates a new landscape for clinical evaluation and future translation of such compounds.

胰腺导管腺癌（PDAC）是一种主要（约95%）由KRAS突变导致的癌症，预后极差，部分原因是其对几乎所有治疗药物都具有很强的内在抗性。PDAC严重依赖KRAS转化的代谢，包括增强的巨胞饮作用和细胞外白蛋白的分解代谢，以维持其增殖和进展。然而，这种转化的代谢是否可用于药物递送，从而为KRAS突变的PDAC中的细胞毒药物开辟治疗窗口，仍有待验证。在本研究中，我们试图通过关注白蛋白分解代谢的两个关键调节因子——KRAS和新生儿Fc受体（FcRn）对PDAC对阿霉素（DOX，一种细胞毒药物模型）和白蛋白结合阿霉素（DOX - ALB）敏感性的影响来回答这个问题。利用具有不同KRAS基因型和FcRn水平的细胞系和细胞衍生的异种移植物，我们证明了KRAS增强的巨胞饮作用和FcRn表达降低使PDAC对DOX - ALB敏感，但对游离的DOX不敏感。在体外和体内比较中，在具有KRAS突变和FcRn水平降低的PDAC中（在所研究的PDAC中这两种情况似乎同时发生），DOX - ALB与游离DOX相比，治疗窗口扩大了约10倍。总之，我们得出结论，白蛋白结合是一种可利用的药物递送策略，它显著为KRAS突变的PDAC治疗中原本无法开发的抗癌药物开辟了治疗窗口，并为这类化合物的临床评估和未来转化创造了新的前景。