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Garrett, Joan
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- Description/Abstract:
- Background: Non-muscle myosin IIA (NMIIA; encoded by MYH9) has been implicated in breast cancer progression; however, its clinical significance and therapeutic potential in HER2-positive (HER2+) breast cancer remain poorly defined. We investigated the clinical significance of NMIIA and evaluated the anti-tumour activity of the selective NMII inhibitor MT-228. Methods: NMIIA expression was evaluated by immunohistochemistry in a cohort of 1,142 patients with early-stage invasive breast cancer. Molecular docking and molecular dynamics simulations were performed to characterize binding of MT-228 to NMIIA. The effects of MT-228 were assessed in breast cancer cell lines using assays of cell viability, migration, three-dimensional invasion, DNA damage, apoptosis, and combination studies with FDA approved HER kinase inhibitors Neratinib and Tucatinib. Results: High NMIIA expression was associated with adverse clinical outcomes in patients with HER2 immunoreactive breast cancer. Computational analyses demonstrated that MT-228 forms favorable binding interactions and stabilized the NMIIA motor domain. MT-228 inhibited cell growth across multiple breast cancer subtypes. In HER2+ cell lines, MT-228 suppressed migration and 3D invasion, increased γH2AX foci formation, caspase-3/7 enzyme activity, and PARP cleavage, and enhanced the anti-proliferative activity of Neratinib and Tucatinib. Conclusions: Our findings identify NMII as a potential therapeutic target in HER2 immunoreactive breast cancer and support further investigation of selective NMII inhibition either alone or in combination with anti-HER therapies.
- Creator/Author:
- Feroz, Wasim and Garrett, Joan
- Submitter:
- Joan Garrett
- License:
- Attribution 4.0 International
- Type:
- Collection
- Description/Abstract:
- Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide, with roughly 41% of CRC cases harboring a KRAS mutation. There have been significant advances with the advent of KRAS-targeted therapies; however, acquired resistance to KRAS-targeted treatments has occurred in other cancers, with mechanisms including increased HER family expression among other receptor tyrosine kinases. HER3, a member of the HER family that is kinase impaired, has been shown to be a resistance mechanism upon inhibition of the HER family and downstream targets including RAS/MEK/ERK and PI3K/AKT. Our study examines whether HER3 and mutant KRAS are viable co-targets. We find that KRAS mutations tend to co-occur with HER3 alterations in a large panel of cancers and in CRCs. Our results show that both total and activated HER3 levels increase in CRC patient derived organoids and cell lines after treatment with KRASG12D targeted agents, indicating that HER3 could be a potential adaptive response mechanism to KRAS-targeted therapy. Further, we found that genetic knock-down of KRAS and HER3 resulted in a statistically significant reduction in growth of CRC cells compared to single knockdown of either KRAS or HER3. We observed that kinase impaired HER3 binding partners, as assessed by immunoprecipitation, is cell dependent with EGFR binding HER3 in one cell line. After co-treating CRC cells with pan-HER inhibitors in combination with MRTX1133, a KRASG12D inhibitor, synergistic and additive effects in reduction in cell growth were observed in a drug-dependent manner. Finally, we found that co-targeting KRASG12D mutant cells with a KRASG12D inhibitor and a HER3 antibody-drug conjugate further reduced cell viability. We posit that co-targeting both KRASG12D and HER3, whether directly or indirectly, is a potential therapeutic strategy in CRC patients.
- Creator/Author:
- Garrett, Joan and Kilroy, Mary Kate
- Submitter:
- Joan Garrett
- License:
- Attribution 4.0 International