Anti‐tumor Activity of PCAIs in 3D Cell Culture and Mice Models

Abstract

PURPOSEOf the four molecular subtypes of breast cancer, TNBC is the most difficult to treat due to its lack of biomarkers and targeted therapies. Metastasis, which is characterized by cancer cell migration and invasion of distal organs, is highly prevalent in TNBC, making the disease harder to manage while lowering survival rates. The PCAIs, developed and modeled around the post‐translational modifications of regulatory proteins such as K‐Ras, were designed to inhibit the interactions of overactive monomeric G‐proteins. These proteins operate downstream of EGFR which is overexpressed in 60% of TNBC cases and are vastly involved in regulating cell survival, motility, apoptosis, and ultimately cancer progression. Previous work in our lab has shown that treatment of various cancer cell lines with PCAIs leads to cell cycle arrest, suppression of cell viability, inhibition of monolayer cell migration and invasion, and induction of caspase 3/7‐mediated apoptotic death. The purpose of this study was to determine the effectiveness of PCAIs at impeding the trademarks of cancer progression in 3D cell culture and in in vivo models.METHODSMDA‐MB‐231 cells were used in 3D cell culture assays to assess the PCAIs' ability to inhibit spheroid formation and invasion while inducing apoptosis. TNBC mice xenografts were used to determine the efficacy of PCAIs in vivo.RESULTSCompounds NSL‐BA‐055 and NSL‐BA‐040 were the most potent of the PCAIs, halting the formation of compact spheroids at 1.0 and 2.0 μM while significantly inhibiting spheroid invasion at 0.2 and 1.0 μM, respectively. Both compounds induced apoptosis and completely obliterated compact TNBC spheroids at 5.0 μM. Five and 10 mg/kg NSL‐BA‐040 inhibited the growth of TNBC xenograft tumors by 60.1 and 71.2%, respectively.CONCLUSIONThe PCAIs' ability to prevent spheroid formation and invasion while inducing spheroid apoptosis suggests their ability to prevent metastasis, tumor formation, growth and potential as effective therapies for TNBC.Support or Funding InformationThe research reported in this publication was supported by the National Cancer Institute (NCI) and National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH) under Grant SC1CA190505 and by the National Institute On Minority Health and Health Disparities (NIMHD) of the NIH under Award Number G12 MD007582 (previous award NIH/NCRR/RCMI G12 RR03020). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.