Rac inhibition as a novel therapeutic strategy for EGFR/HER2 targeted therapy resistant breast cancer

Abstract

Background Even though targeted therapies are available for cancers expressing oncogenic epidermal growth receptor (EGFR) and (or) human EGFR2 (HER2), acquired or intrinsic resistance often confounds therapy success. Common mechanisms of therapy resistance involve activating receptor point mutations and (or) upregulation of signaling downstream of EGFR/HER2 to Akt and (or) mitogen activated protein kinase (MAPK) pathways. However, additional pathways of resistance may exist thus, confounding successful therapy. Methods To determine novel mechanisms of EGFR/HER2 therapy resistance in breast cancer, gefitinib or lapatinib resistant variants were created from SKBR3 breast cancer cells. Syngenic therapy sensitive and resistant SKBR3 variants were characterized for mechanisms of resistance by mammosphere assays, viability assays, and western blotting for total and phospho proteins. Results Gefitinib and lapatinib treatments reduced mammosphere formation in the sensitive cells, but not in the therapy resistant variants, indicating enhanced mesenchymal and cancer stem cell-like characteristics in therapy resistant cells. The therapy resistant variants did not show significant changes in known therapy resistant pathways of AKT and MAPK activities downstream of EGFR/HER2. However, these cells exhibited elevated expression and activation of the small GTPase Rac, which is a pivotal intermediate of GFR signaling in EMT and metastasis. Therefore, the potential of the Rac inhibitors EHop-016 and MBQ-167 to overcome therapy resistance was tested, and found to inhibit viability and induce apoptosis of therapy resistant cells. Conclusions Rac inhibition may represent a viable strategy for treatment of EGFR/HER2 targeted therapy resistant breast cancer.

Rac1 as a Target to Treat Dysfunctions and Cancer of the Bladder

“…The latter compound has been shown to inhibit Rac1/2/3 in MDA-MB-231 triple-negative breast cancer cells (IC 50 = 103 nM) in addition to inhibiting the other GTPase Cdc42 (cell division control protein 42) (IC 50 = 78 nM) [ 134 ]. It is a potent anticancer agent, at least at the preclinical level, currently positioned to treat triple-negative breast cancer [ 135 , 136 ]. However, the scope of tumors addressable with such a pan-Rac inhibitor is large and includes breast, colon, liver, lung, and other tumor types [ 132 ].…”

Carboranes as unique pharmacophores in antitumor medicinal chemistry

“…EGFR/ErbB1 is a member of the ErbB protein family of RTKs. 194 , 195 , 196 , 197 The signaling pathways regulated by EGF-EGFR play key roles in regulating basic cell functions, such as cell proliferation, survival, differentiation, and migration ( Figure 7 C). 194 , 198 EGFR-mediated cellular events are interfered with by inhibiting EGF from binding to EGFR on the surface of cancer cells.…”

Diosgenin and Monohydroxy Spirostanol from Prunus amygdalus var amara Seeds as Potential Suppressors of EGFR and HER2 Tyrosine Kinases: A Computational Approach

“…Therefore, it is important to consider the major evasion mechanisms, such as the heregulin-EGFR-HER3 autocrine signaling axis that can mediate acquired lapatinib resistance in HER2+ breast cancer models [ 11 ]. Understanding the roles of EGFR and HER2 in cancer proliferation is crucial for developing effective therapies that can target these proteins and overcome drug resistance [ 17 , 18 , 19 ]. TKIs (tyrosine kinase inhibitors) such as gefitinib, erlotinib, neratinib, and afatinib, are used to target EGFR/HER2 [ 17 , 20 , 21 ].…”

“…These four drugs have been associated with adverse impacts that can effectively influence patient health [ 17 , 20 , 21 ]. Lapatinib is a dual suppressor of EGFR and HER2 that has been used in clinical trials [ 19 , 22 ]. Lapatinib is an irreversible suppressor of chemotherapeutics [ 19 , 22 ] and was selected as a regarded drug in the current work.…”

“…Lapatinib is a dual suppressor of EGFR and HER2 that has been used in clinical trials [ 19 , 22 ]. Lapatinib is an irreversible suppressor of chemotherapeutics [ 19 , 22 ] and was selected as a regarded drug in the current work.…”