Cell death-based treatment of lung adenocarcinoma

Abstract

The most common type of lung cancer is adenocarcinoma (ADC), comprising around 40% of all lung cancer cases. In spite of achievements in understanding the pathogenesis of this disease and the development of new approaches in its treatment, unfortunately, lung ADC is still one of the most aggressive and rapidly fatal tumor types with overall survival less than 5 years. Lung ADC is often diagnosed at advanced stages involving disseminated metastatic tumors. This is particularly important for the successful development of new approaches in cancer therapy. The high resistance of lung ADC to conventional radiotherapies and chemotherapies represents a major challenge for treatment effectiveness. Here we discuss recent advances in understanding the molecular pathways driving tumor progression and related targeted therapies in lung ADCs. In addition, the cell death mechanisms induced by different treatment strategies and their contribution to therapy resistance are analyzed. The focus is on approaches to overcoming drug resistance in order to improve future treatment decisions.

Fig. 1. The EGFR-TKI resistance mechanisms and related targeted therapies in lung ADC

The resistance to the EGFR-TKI involves activation of several pathways. One of the mechanisms depends on the appearance of secondary mutations in EGFR, such as Thr790Met, L858R or deletion of exon 19. Another one includes activations of bypass signaling pathways such as PI3CA, MET, ERK, HER2 or AXL. Low mRNA level or polymorphism of pro-apoptotic protein Bim could also mediate intrinsic resistance of lung ADC to EGFR inhibitors. Alternatively, autophagy stimulation might sustain resistance to the RTK inhibitors (erlotinib and gefitinib) in these tumors. The inhibition of autophagy with chloroquine could accelerate RTKI-induced apoptosis and overcome resistance of lung ADC cells. For more detail, see the text

Fig. 2. Link between the immune system state and response of immune checkpoint molecule inhibitors: CTLA-4 inhibitors (ipilimumab and tremelimumab), PD-1 inhibitors (pembrolizumab and nivolumab), PD-L1 inhibitors (atezolizumab and durvalumab)

For more detail, see the text