EGFR-TKIs resistance via EGFR-independent signaling pathways

Abstract

Tyrosine kinase inhibitors (TKIs)-treatments bring significant benefit for patients harboring epidermal growth factor receptor (EGFR) mutations, especially for those with lung cancer. Unfortunately, the majority of these patients ultimately develop to the acquired resistance after a period of treatment. Two central mechanisms are involved in the resistant process: EGFR secondary mutations and bypass signaling activations. In an EGFR-dependent manner, acquired mutations, such as T790 M, interferes the interaction between TKIs and the kinase domain of EGFR. While in an EGFR-independent manner, dysregulation of other receptor tyrosine kinases (RTKs) or abnormal activation of downstream compounds both have compensatory functions against the inhibition of EGFR through triggering phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) signaling axes. Nowadays, many clinical trials aiming to overcome and prevent TKIs resistance in various cancers are ongoing or completed. EGFR-TKIs in accompany with the targeted agents for resistance-related factors afford a promising first-line strategy to further clinical application.

MiRNA-7 enhances erlotinib sensitivity of glioblastoma cells by blocking the IRS-1 and IRS-2 expression

“…The EGFR, a transmembrane glycoprotein belonging to the ErbB family of RTKs, is over‐expressed in different types of malignant tumours . EGFR amplification and over‐expression were found in more than 60% of primary glioblastomas, which leads to excitation of several signalling pathways, including PI3K/Akt and Ras/Raf/MAPK and subsequently proliferation, invasion and survival of tumour cells . Some reports have shown that expression of IRS‐1 and IRS‐2, two upstream modulators of IGF‐1R/Akt pathway, are elevated in various types of cancer cells .…”

“…[6] EGFR amplification and over-expression were found in more than 60% of primary glioblastomas, which leads to excitation of several signalling pathways, including PI3K/Akt and Ras/Raf/MAPK and subsequently proliferation, invasion and survival of tumour cells. [4,[7][8][9][10] Some reports have shown that expression of IRS-1 and IRS-2, two upstream modulators of IGF-1R/Akt pathway, are elevated in various types of cancer cells. [17][18][19] Other reports have demonstrated that Akt activity is regulated through a combination of EGFR and IGF-1R pathways, and inhibition of EGFR causes the activation of the IGF-1R pathway.…”

“…Amplification and over‐expression of EGFR gene were found in more than 60% of primary glioblastomas and are believed to be linked to the proliferation, growth, angiogenesis and invasiveness in glioma cells . Ligand‐dependent EGFR activation leads to the excitation of two primary downstream signalling pathways: both of PI3‐kinase (PI3K)/Akt and Ras/Raf/mitogen‐activated protein kinase (MAPK), which are involved in the proliferation, migration and drug resistance of cancer cells . Therefore, the EGFR is considered as a major target for molecular‐targeting therapy.…”

“…[4,8] Ligand-dependent EGFR activation leads to the excitation of two primary downstream signalling pathways: both of PI3-kinase (PI3K)/Akt and Ras/Raf/mitogen-activated protein kinase (MAPK), which are involved in the proliferation, migration and drug resistance of cancer cells. [7,9,10] Therefore, the EGFR is considered as a major target for molecular-targeting therapy. Erlotinib, a small-molecule inhibitor of EGFR, has been developed as a therapeutic agent for glioblastoma therapy.…”

Identifying Tumorigenesis and Prognosis-Related Genes of Lung Adenocarcinoma: Based on Weighted Gene Coexpression Network Analysis

“…A growing body of evidence indicates that although gene alterations accumulate during the development of LUADs, a proportion of LUADs are primarily driven by single gene alterations such as epidermal growth factor receptor (EGFR) mutation and (anaplastic lymphoma kinase) ALK or ROS1 rearrangement, which are also known as driven genes [5][6][7][8].…”