The RAS ‐related GTP ase RHOB confers resistance to EGFR ‐tyrosine kinase inhibitors in non‐small‐cell lung cancer via an AKT ‐dependent mechanism

Abstract

Although lung cancer patients harboring EGFR mutations benefit from treatment with EGFR‐tyrosine kinase inhibitors (EGFR‐TKI), most of them rapidly relapse. RHOB GTPase is a critical player in both lung carcinogenesis and the EGFR signaling pathway; therefore, we hypothesized that it could play a role in the response to EGFR‐TKI. In a series of samples from EGFR‐mutated patients, we found that low RHOB expression correlated with a good response to EGFR‐TKI treatment while a poor response correlated with high RHOB expression (15.3 versus 5.6 months of progression‐free survival). Moreover, a better response to EGFR‐TKI was associated with low RHOB levels in a panel of lung tumor cell lines and in a lung‐specific tetracycline‐inducible EGFRL 858R transgenic mouse model. High RHOB expression was also found to prevent erlotinib‐induced AKT inhibition in vitro and in vivo. Furthermore, a combination of the new‐generation AKT inhibitor G594 with erlotinib induced tumor cell death in vitro and tumor regression in vivo in RHOB‐positive cells. Our results support a role for RHOB/AKT signaling in the resistance to EGFR‐TKI and propose RHOB as a potential predictor of patient response to EGFR‐TKI treatment.

Identification of potential biomarkers in cervical cancer with combined public mRNA and miRNA expression microarray data analysis

“…RhoB may be a tumor suppressor as its expression level is decreased in a number of tumor cell types ( 25 ). Its expression is more downregulated in increasingly aggressive tumors, and the loss of RhoB is associated with a decreased overall survival time in certain types of cancer ( 26 – 28 ). RhoB is not mutated in all types of cancer; however, its altered expression and activity may be critical in cancer progression and the response to therapy.…”

“…RhoB is not mutated in all types of cancer; however, its altered expression and activity may be critical in cancer progression and the response to therapy. For example, RhoB expression is predictive of an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) response; a EGFR-TKI/Akt inhibitor combination provides a clinical advantage in preventing resistance to EGFR-TKI for RhoB-positive tumor patients ( 26 ). A number of studies have identified a loss of RhoB expression in head, neck, gastric, renal and lung cancer ( 29 – 31 ).…”

Notch inhibition overcomes resistance to tyrosine kinase inhibitors in EGFR-driven lung adenocarcinoma

“…Tumors were analyzed from patients with EGFR mutations and treated with EGFR TKIs. Seventy-five patients were being treated at Toulouse University Hospital (52), and 4 had participated in the MOSCATO (NCT01566019) or MATCH-R (NCT02517892) clinical trials at the Institut Gustave Roussy.…”

Spatiotemporal Control of Intracellular Membrane Trafficking by Rho GTPases

“…Similarly, in RhoB-null vascular smooth muscle cells, PDGF receptor trafficking to the late endosomal compartment and Akt activation were compromised, and this was later shown to also impair Cdc42 and Rac transport to the PM [124,161]. Intriguingly, a recent study also showed that high expression levels of the small GTPase RhoB in non-small-cell lung cancer (NSCLC)conferred resistance to EGFR-TKIs by enhancing Akt activation [162], although it was not investigated whether this was connected to altered EGFR trafficking. Since Akt signaling emanates from both the PM and endomembranes and RhoB is also involved in the nuclear translocation of Akt [163], the precise function of RhoB depends on its location, the available effector proteins and the nature of activated downstream signaling pathways in the cells.…”

“…DLC3 was reported to be downregulated in various types of cancers, including breast, prostate, kidney, lung, and ovarian [165]. DLC3 knockdown prevented EGFR degradation and enhanced Akt activation by trapping the receptor in EEA1-positive endosomes [41], making it tempting to speculate that reduced DLC3 expression might also confer EGFR-TKI resistance as described for lung cancers overexpressing RhoB [162]. DLC3 depletion in breast cancer cells also caused aberrant Rab4-dependent matrix metalloproteinase recycling and invadopodia matrix degradation in a RhoB-and actin-dependent manner [41,42,166].…”