Semaphorin 3A Suppresses Tumor Growth and Metastasis in Mice Melanoma Model

<div><h3>Background</h3><p>Recent understanding on cancer therapy indicated that targeting metastatic signature or angiogenic switch could be a promising and rational approach to combat cancer. Advancement in cancer research has demonstrated the potential role of various tumor suppressor proteins in inhibition of cancer progression. Current studies have shown that axonal sprouting inhibitor, semaphorin 3A (Sema 3A) acts as a potent suppressor of tumor angiogenesis in various cancer models. However, the function of Sema 3A in regulation of melanoma progression is not well studied, and yet to be the subject of intense investigation.</p> <h3>Methodology/Principal Findings</h3><p>In this study, using multiple <em>in vitro</em> and <em>in vivo</em> approaches we have demonstrated that Sema 3A acts as a potent tumor suppressor <em>in vitro</em> and <em>in vivo</em> mice (C57BL/6) models. Mouse melanoma (B16F10) cells overexpressed with Sema 3A resulted in significant inhibition of cell motility, invasiveness and proliferation as well as suppression of <em>in vivo</em> tumor growth, angiogenesis and metastasis in mice models. Moreover, we have observed that Sema 3A overexpressed melanoma clone showed increased sensitivity towards curcumin and Dacarbazine, anti-cancer agents.</p> <h3>Conclusions</h3><p>Our results demonstrate, at least in part, the functional approach underlying Sema 3A mediated inhibition of tumorigenesis and angiogenesis and a clear understanding of such a process may facilitate the development of novel therapeutic strategy for the treatment of cancer.</p> </div

HER3 signaling and targeted therapy in cancer

ERBB family members including epidermal growth factor receptor (EGFR) also known as HER1, ERBB2/HER2/Neu, ERBB3/HER3 and ERBB4/HER4 are aberrantly activated in multiple cancers and hence serve as drug targets and biomarkers in modern precision therapy. The therapeutic potential of HER3 has long been underappreciated, due to impaired kinase activity and relatively low expression in tumors. However, HER3 has received attention in recent years as it is a crucial heterodimeric partner for other EGFR family members and has the potential to regulate EGFR/HER2-mediated resistance. Upregulation of HER3 is associated with several malignancies where it fosters tumor progression via interaction with different receptor tyrosine kinases (RTKs). Studies also implicate HER3 contributing significantly to treatment failure, mostly through the activation of PI3K/AKT, MAPK/ERK and JAK/STAT pathways. Moreover, activating mutations in HER3 have highlighted the role of HER3 as a direct therapeutic target. Therapeutic targeting of HER3 includes abrogating its dimerization partners’ kinase activity using small molecule inhibitors (lapatinib, erlotinib, gefitinib, afatinib, neratinib) or direct targeting of its extracellular domain. In this review, we focus on HER3-mediated signaling, its role in drug resistance and discuss the latest advances to overcome resistance by targeting HER3 using mono- and bispecific antibodies and small molecule inhibitors

PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects

The phospatidylinositol-3 kinase (PI3K) pathway is a crucial intracellular signaling pathway which is mutated or amplified in a wide variety of cancers including breast, gastric, ovarian, colorectal, prostate, glioblastoma and endometrial cancers. PI3K signaling plays an important role in cancer cell survival, angiogenesis and metastasis, making it a promising therapeutic target. There are several ongoing and completed clinical trials involving PI3K inhibitors (pan, isoform-specific and dual PI3K/mTOR) with the goal to find efficient PI3K inhibitors that could overcome resistance to current therapies. This review focuses on the current landscape of various PI3K inhibitors either as monotherapy or in combination therapies and the treatment outcomes involved in various phases of clinical trials in different cancer types. There is a discussion of the drug-related toxicities, challenges associated with these PI3K inhibitors and the adverse events leading to treatment failure. In addition, novel PI3K drugs that have potential to be translated in the clinic are highlighted

Abstract 5412: Role of her3 mutations on breast cancer oncogenesis

Abstract We sought to determine if naturally occurring mutations in HER3 could drive oncogenic growth of HER3KO HER2+ HCC1569 cells in which endogenous HER3 has been eliminated via CRISPR-Cas9. A series of HER3 mutations identified in breast cancer patients (F94L, V104L, G284R, D297Y, T355I, and E928G) were introduced using lentiviral transduction and stable cell lines were generated in HER3KOHCC1569 cells via puromycin selection. We identified HER3V104L mutation to have higher cell proliferation and higher p-HER3 expression compared to wild-type (wt) and empty-vector (EV) HER3. We observed that HCC1569HER3KO cells stably expressing WT and V104L were sensitive to increasing doses of neratinib (0.1-0.5 µM) concentration. Next we analyzed if this mutation rendered resistance to the recently FDA- approved irreversible HER2 tyrosine kinase inhibitor, tucatinib. Our data indicated that both that V104L cells were sensitive to higher concentration of tucatinib compared to neratinib. In parallel experiments, we utilized COS7 cells to examine the signaling properties of HER3V104L. Our data indicated that transient transfection of COS7 cells with HER3V104L mutant significantly induces p-HER3/p-AKT and p-HER2 expression compared to WT HER3 in a ligand dependent manner. In addition, we observed that the V104L mutation stabilizes HER3 protein expression independent of HER2 and ligand stimulation. Experiments are ongoing to determine whether V104L induced HER3 stabilization and downstream signaling activation is dependent on HER3 binding partners including EGFR, HER2 or HER4. We also aim to understand how the V104L mutation stabilizes HER3 expression. Structural modeling of V104L mutation will provide insight about the mechanism of stabilization of the HER3 protein. We will use MCF10A and HEK293 cells to determine the effect of the V104L mutation on HER3 expression and downstream signaling. We also aim to decipher the signaling mechanism that drives the oncogenic potential of V104L mutation. In addition, we are using various PDXs with different HER3 mutations to determine other driver HER3 mutations in breast cancer and how this can be targeted in the clinic using HER targeted therapy. Citation Format: Rosalin Mishra, Mary Kate Kilroy, Hima Patel, Samar Alanazi, Joan T. Garrett. Role of her3 mutations on breast cancer oncogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5412.</jats:p

PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects

The phospatidylinositol-3 kinase (PI3K) pathway is a crucial intracellular signaling pathway which is mutated or amplified in a wide variety of cancers including breast, gastric, ovarian, colorectal, prostate, glioblastoma and endometrial cancers. PI3K signaling plays an important role in cancer cell survival, angiogenesis and metastasis, making it a promising therapeutic target. There are several ongoing and completed clinical trials involving PI3K inhibitors (pan, isoform-specific and dual PI3K/mTOR) with the goal to find efficient PI3K inhibitors that could overcome resistance to current therapies. This review focuses on the current landscape of various PI3K inhibitors either as monotherapy or in combination therapies and the treatment outcomes involved in various phases of clinical trials in different cancer types. There is a discussion of the drug-related toxicities, challenges associated with these PI3K inhibitors and the adverse events leading to treatment failure. In addition, novel PI3K drugs that have potential to be translated in the clinic are highlighted.</jats:p