Mechanistic insights into acquired drug resistance in epidermal growth factor receptor mutation-targeted lung cancer therapy

Abstract

Oncogenic mutation of epidermal growth factor receptor kinase domain is strongly associated with clinical response to tyrosine kinase inhibitors in non-small-cell lung carcinoma. Despite an initial encouraging response, patients eventually develop drug resistance and relapse. Great efforts have been made to identify the molecular mechanisms of drug resistance. With the recognition of cancer as a whole complex system, here it is proposed that cancer may evolve drug resistance in a cancer-cell-autonomous manner as well as a non-cancer-cell-autonomous manner. The former mainly arises at three levels: the robustness of the epidermal growth factor receptor signaling network; cancer epigenetic changes; or cancer genetic alteration, which may be dependent on the therapeutics methods and treatment duration. As cancer stroma plays an essential role in lung cancerigenesis, we further discuss the potential mechanisms for drug resistance development in a non-cancer-cell-autonomous manner, which may arise from the interaction between cancer cells and cancer stroma, including stromal cells and extracellular matrix.

Figure 1

Schematic illustration of the potential molecular mechanisms of drug resistance development in epidermal growth factor receptor (EGFR) mutation‐targeted lung cancer therapy in a cancer‐cell‐autonomous and non‐cancer‐cell‐autonomous manner. The robustness of the EGFR signaling network, epigenetic changes, and genetic alterations in cancer cells contribute to drug resistance in a cancer‐cell‐autonomous manner. The interaction between cancer cells and cancer stroma, including stromal cells and ECM, contributes to drug resistance in a non‐cancer‐cell‐autonomous manner.

Figure 2

Simplified schematic illustration of the epidermal growth factor receptor (EGFR) signaling network. After ligand stimulation, EGFR is activated and directly transmits signals to downstream pathways, including the phosphatidylinositol‐3‐kinase (PI3K)/3‐phosphoinositide‐dependent protein kinase (PDK)/v‐akt murine thymoma viral oncogene homolog (AKT)/mammalian target of rapamycin (mTOR) and signal transducer and activator of transcription 3/5 (STAT3/5) pathways for cell survival, and the rat sarcoma viral oncogene homolog (RAS)/v‐raf‐1 murine leukemia viral oncogene homolog (RAF)/MAPK/ERK kinase (MEK)/MAPK pathway for cell proliferation. Phosphatase and tensin homolog (PTEN) inhibits AKT activity through PDK. The EGFR pathway cross‐talks with other signaling pathways: either hepatocyte growth factor receptor (MET) activation by hepatocyte growth factor (HGF) stimulation or EGFR activation is able to transmit signals through erythroblastic leukemia viral (v‐erb‐b) oncogene homolog 3 (ERBB3) and results in the activation of the PI3K/AKT pathway; and G‐protein coupled receptor (GPCR) activation enhances EGFR signaling through a disintegrin and metalloproteinases (ADAMs) that shed pro‐heparin‐binding EGF‐like growth factor (HB‐EGF) and increase the amount of HB‐EGF. As well as the cross‐talk with GPCR signaling, insulin‐like growth factor‐1 receptor (IGF‐1R) signaling through insulin receptor substrate (IRS) activates the PI3K/PDK/AKT/mTOR and RAS/RAF/MEK/MAPK pathways, which are commonly shared by EGFR signaling. GRB2, growth factor receptor‐bound 2; P, phosphorylation; SOS, son of sevenless homolog; P85, phosphatidylinositol 3‐kinase regulatory subunit.

Figure 3

Positive and negative feedback loops in the epidermal growth factor receptor (EGFR) signaling pathway. (a) Two positive feedback loops. First, the activation of proline‐rich tyrosine kinase 2 (PYK2)/v‐src sarcoma viral oncogene homolog (c‐Src) activates a disintegrin and metalloproteinases (ADAMs) which shed pro‐heparin‐binding EGF‐like growth factor (HB‐EGF) and results in an increase in HB‐EGF and enhancement of EGFR signaling. Second, phospholipase Cγ (PLCγ) activation produces diacylglycerol (DAG) from PI4,5‐P2, which consecutively activates downstream PKC, phospholipase D (PLD), and phosphatidylinositol‐5‐kinase (PI5K). Activation of PI5K produces PI4,5‐P2 from PI4‐P and thus enhances the signaling. (b) Six negative feedback loops. The activation of protein tyrosine phosphatases (SHP‐1 and SHP‐2) inhibits EGFR signaling; the activation of ERK1 and ERK2, or ribosomal protein S6 kinase (RSK2) inhibits the son of sevenless homolog (SOS); recruitment of Casitas B‐lineage lymphoma proto‐oncogene (c‐Cbl) by growth factor receptor‐bound protein (GRB2) mediates EGFR degradation. RAS, rat sarcoma viral oncogene homolog.