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Review
. 2018 Feb 19;17(1):53.
doi: 10.1186/s12943-018-0793-1.

EGFR-TKIs resistance via EGFR-independent signaling pathways

Qian Liu  1 , Shengnan Yu  1 , Weiheng Zhao  1 , Shuang Qin  1 , Qian Chu  2 , Kongming Wu  3
Affiliations
Review

EGFR-TKIs resistance via EGFR-independent signaling pathways

Qian Liu et al. Mol Cancer. .

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.

Keywords: Bypass signalings; Downstream compounds; Drug resistance; EGFR; ErbB; RTKs; TKIs.

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Figures

Fig. 1
Fig. 1
Secondary RTKs-induced EGFR-TKIs resistance. EGFR could trigger downstream PI3K/Akt and MAPK signaling axes which in turn stimulate the transcription factors to drive the associated genes expression which are related with proliferation, angiogenesis, invasion and metastasis. TKIs inhibit EGFR-drived signal transduction by interacting with the tyrosine kinase domain of EGFR. Other RTKs are involved in the development of TKIs resistance via a EGFR-indepenfent way: 1. Amplification of MET activates PI3K through transactivating ErbB3; 2. HGF overexpression; 3. ErbB2 amplification; 4. ErbB3 activation; 5. IGF1R activation by IGF binding or IGFBP reduction; 6. AXL activation; 7. FGFR1 activation
Fig. 2
Fig. 2
Alternative downstream compounds-induced EGFR-TKIs resistance. 1. PTEN loss: suppressed HGR1 downregulates PTEN expression which in general inhibits the PI3K/Akt activation. 2. PIK3CA mutation-drived abnormal activation of PI3K pathway. 3. BRAF mutation-drived abnormal activation of MAPK signaling axis
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