Early Steps of Resistance to Targeted Therapies in Non-Small-Cell Lung Cancer

Abstract

Lung cancer is the leading cause of cancer-related deaths among men and women worldwide. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective therapies for advanced non-small-cell lung cancer (NSCLC) patients harbouring EGFR-activating mutations, but are not curative due to the inevitable emergence of resistances. Recent in vitro studies suggest that resistance to EGFR-TKI may arise from a small population of drug-tolerant persister cells (DTP) through non-genetic reprogramming, by entering a reversible slow-to-non-proliferative state, before developing genetically derived resistances. Deciphering the molecular mechanisms governing the dynamics of the drug-tolerant state is therefore a priority to provide sustainable therapeutic solutions for patients. An increasing number of molecular mechanisms underlying DTP survival are being described, such as chromatin and epigenetic remodelling, the reactivation of anti-apoptotic/survival pathways, metabolic reprogramming, and interactions with their micro-environment. Here, we review and discuss the existing proposed mechanisms involved in the DTP state. We describe their biological features, molecular mechanisms of tolerance, and the therapeutic strategies that are tested to target the DTP.

Keywords: EGFR-TKI; drug-tolerant persisters; lung cancer; targeted therapies.

Figure 1

Evolution of identification of actionable alterations and appropriate targeted therapies in the standard of care in advanced non-small-cell lung cancer (NSCLC). (A) The discovery of oncogenic drivers in NSCLC led to the development of more personalised medicine and improved response rate and overall survival over the years. (B) Increasing number of FDA-approved drugs for treatment of oncogene-addicted NSCLC.

Figure 2

The vicious circle of resistances to EGFR-TKI in NSCLC. Although new targeted therapies are designed to counteract the resistance mechanisms developed with previous-generation EGFR-TKI, similar resistance inevitably emerges, resulting in little improvement to overall survival in patients.

Figure 3

Schematic representation of the clinical response to targeted therapy in NSCLC patients. Primary resistance (red line) is characterised by a lack of initial response and a fast progression. Most patients display an initial response (blue line), with sometimes an apparently complete clearance of the tumour, although minimal residual disease persists and ultimately causes relapse in the vast majority of patients. Two hypotheses might explain the appearance of resistance for both primary and acquired resistance and might even co-exist within the same tumour. The Darwinian model suggests that, before the treatment, a population of sensitive cells (blue) co-exist with resistant cells (red) in treatment-naïve tumours, and pre-existing resistant cells are selected during treatment. The Lamarckian model suggests that a rare subpopulation of cells survives under treatment as the drug-tolerant persisters (DTPs). DTP cells exhibit non-genetic mechanisms of tolerance, slow-cycling capacities and a reversible phenotype, and could mimic the minimal residual disease phase observed in patients. DTP may eventually acquire drug-resistant mechanisms (green) and regain proliferative capacities. To study the minimal residual disease, several models are being used: most often cells treated with targeted therapies; xenograft models implanted in treated mice; and very rarely using biopsies from patients under treatment.

Figure 4

Hallmarks of drug tolerance. Drug-tolerant persisters (DTPs) share biological features, such as a reversible and plastic phenotype, slow-cycling capacities, and a senescent-like phenotype. The molecular mechanisms that drive the establishment and the maintenance of DTPs are a global chromatin remodelling with epigenetic modifications, the activation of anti-apoptotic and alternative cell-survival signalling pathways, metabolic reprogramming, and micro-environment hijacking.

Figure 5

Therapeutic perspectives to improve targeted therapies outcome un lung cancer. Potential strategies to prevent the relapse include the maintenance and stabilisation of the DTP stage, the eradication of the DTP population after their establishment by targeting their key regulators, or the impediment to DTP generation. Several clinically relevant strategies are being tested.