Abstract
The identification of specific epidermal growth factor receptor (EGFR)-activating mutations heralded a breakthrough in non-small-cell lung cancer (NSCLC) treatments, with the subsequent development of EGFR-tyrosine kinase inhibitor (TKIs) becoming the first-line therapy for patients harboring EGFR mutations. However, acquired resistance to EGFR-TKIs inevitably occurs in patients following initial TKI treatment, leading to disease progression. Various mechanisms are behind the acquired resistance, and mainly include (1) target gene modification, (2) alternative parallel pathway activation, (3) downstream pathway activation, and (4) histological/phenotypic transformation. Approaches to combat the acquired resistance have been investigated according to these mechanisms. Newer generations of TKIs have been developed to target the secondary/tertiary EGFR mutations in patients with acquired resistance. In addition, combination therapies have been developed as another promising strategy to overcome acquired resistance through the activation of other signaling pathways. Thus, in this review, we summarize the mechanisms for acquired resistance and focus on the potential corresponding therapeutic strategies for acquired resistance.
Highlights
Lung cancer remains one of the most malignant cancers in the world, with about 1.8 million reported lung-cancer-related deaths in 2018, accounting for nearly one-fifth of all cancer-related deaths that year [1]
67% and 87%, and PFS was 22.1 and 19.3 months, respectively [39]. These results are more in line with the efficacy of erlotinib or afatinib in the first line, indicating that osimertinib can serve in the first-line treatment for non-small-cell lung cancer (NSCLC)
At ASCO 2018, Okada et al reported a good safety profile for osimertinib plus carboplatin-pemetrexed combination treatment in 24 T790M-positive NSCLC patients who progressed to treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKIs) [130]
Summary
Lung cancer remains one of the most malignant cancers in the world, with about 1.8 million reported lung-cancer-related deaths in 2018, accounting for nearly one-fifth of all cancer-related deaths that year [1]. About 85% of those cases are diagnosed as non-small-cell lung cancer (NSCLC), and up to 84% of those NSCLC patients suffer from advanced stage cancer and present with metastasis [2] Among these NSCLC patients, an epidermal growth factor receptor (EGFR)-activating mutation is present in up to 50% Asians and 15% Caucasians, representing the underlying cause. In addition to EGFR, other types of receptor tyrosine kinases, such as mesenchymal–epithelial transition factor (MET), hepatocyte growth receptors (HGFs), insulin-like growth factors receptors (IGFRs), fibroblast growth factor receptors (FGFRs), and vascular endothelial growth factor receptors (VEGFRs), can contribute to the activation of a bypassing or downstream signaling pathway, leading to acquired resistance [6]. We summarize the knowledge regarding mechanisms of drug resistance and outline the latest therapeutic strategies used to overcome this problem
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