Mechanisms of EGFR-TKI-Induced Apoptosis and Strategies Targeting Apoptosis in EGFR-Mutated Non-Small Cell Lung Cancer

Abstract

Homeostasis is achieved by balancing cell survival and death. In cancer cells, especially those carrying driver mutations, the processes and signals that promote apoptosis are inhibited, facilitating the survival and proliferation of these dysregulated cells. Apoptosis induction is an important mechanism underlying the therapeutic efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) for EGFR-mutated non-small cell lung cancer (NSCLC). However, the mechanisms by which EGFR-TKIs induce apoptosis have not been fully elucidated. A deeper understanding of the apoptotic pathways induced by EGFR-TKIs is essential for the developing novel strategies to overcome resistance to EGFR-TKIs or to enhance the initial efficacy through therapeutic synergistic combinations. Recently, therapeutic strategies targeting apoptosis have been developed for cancer. Here, we review the state of knowledge on EGFR-TKI-induced apoptotic pathways and discuss the therapeutic strategies for enhancing EGFR-TKI efficiency. We highlight the great progress achieved with third-generation EGFR-TKIs. In particular, combination therapies of EGFR-TKIs with anti-vascular endothelial growth factor/receptor inhibitors or chemotherapy have emerged as promising therapeutic strategies for patients with EGFR-mutated NSCLC. Nevertheless, further breakthroughs are needed to yield an appropriate standard care for patients with EGFR-mutated NSCLC, which requires gaining a deeper understanding of cancer cell dynamics in response to EGFR-TKIs.

EGFR Mutation and FHIT Methylation: Inverse Relationship in Patients with Lung Adenocarcinoma and Tuberculosis

“…Advancements in our understanding of cell signaling pathways have revealed genetic and regulatory abnormalities contributing to tumor formation, including EGFR, expressed in various normal epithelial, mesenchymal, and neurogenic tissues [21,22] . Overexpression of EGFR has been linked to the development of several human malignancies, including NSCLC [23] .…”

Cancer Therapy Resistance: Choosing Kinase Inhibitors

“…Researchers are focused on developing alternative therapies that can collaborate constructively with existing treatments and improve the current approaches. Antioxidant therapies leading to reactive oxygen species inhibition, vascular growth factor receptor (VEGFR) inhibitors, or BH3 mimetic inhibitors (venetoclax) decrease TKI resistance [ 11 , 12 ]. Additionally, strategies aimed at degrading the BCR-ABL1 protein were tested using PROTAC (proteolysis-targeting chimera) technology, which demonstrated efficiently inhibited proliferation and induced apoptosis in vitro [ 13 ].…”

Cetuximab chemotherapy resistance: Insight into the homeostatic evolution of head and neck cancer (Review)

“…Pleiotropic functions of EGFR in HNSCC and other tumors are associated with MAPK/ERK (proliferation, immunosuppression, angiogenesis) ( 88 , 89 ), PI3K/AKT (cell survival and proliferation; apoptosis evasion) ( 89 , 90 ), JAK/STAT (cell growth, development, differentiation and survival) ( 91 ) and phospholipase (PLC) C-γ-1/protein kinase C (PKC) (proliferation, migration) ( 92 , 93 ). Particularly when mutated or overexpressed in HNSCC, EGFR has protumorigenic and prometastatic roles associated with nutrient uptake and biosynthesis, proliferation, inflammation, cell survival, migration and invasion.…”