Primary and Acquired Resistance in Lung Cancer

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Background

Lung cancer is one of the leading causes of cancer-related death worldwide with a prevalence of advanced stage in up to 70% of cases and a five-year survival reached in only 5-10% of cases. Targeted therapies and immunotherapy have greatly improved the management of patients with advanced non-small cell lung cancer (NSCLC), particularly adenocarcinoma, and current diagnostic algorithms are based on the molecular analysis of several biomarkers necessary to tailor therapy.

In detail, patients harboring sensitive driver alterations within the oncogenes EGFR, BRAF, ALK, ROS1, RET and NTRK1/2/3 can be treated with approved kinase inhibitors (KIs). In addition, drugs against MET, KRAS G12C and other markers are providing interesting results across different clinical trials.

Targeted therapies have greatly improved therapeutic options for NSCLC, but resistance inevitably occurs usually after one year of treatment and some patients, although harboring sensitive alterations, never respond to treatment.

It is clear that the definition of oncogene addiction and the evaluation of single biomarkers are not enough to delineate tumor molecular landscape and more efforts are necessary to better elucidate resistance mechanisms. Both primary and acquired resistances have always constituted serious challenges in the context of lung cancer precision medicine. Overall, resistance mechanisms can be target dependent (presence of secondary alterations within the driver oncogene) or target independent (activation of by-pass signaling pathways) and it is not rare to observe resistance mechanism overlaps.

The recent introduction of next-generation sequencing (NGS) techniques and the use of liquid biopsy have made it easier to study resistance mechanisms and particularly the dynamic and heterogeneous temporal and spatial tumor evolution under treatment pressure. However, it is not always easy to translate molecular findings into clinical practice. On one hand, an accurate molecular description of resistance mechanisms is mandatory to improve patient management, leading to more appropriate treatment regimens, on the other hand, molecular testing strategy to define resistance mechanisms still need optimization and the collection of more clinical data is warranted to better understand tumor behavior and escape strategies.

In the context of NSCLC precision medicine primary and secondary resistance mechanisms directly impact prognosis and therapy response, thus constituting a challenge often difficult to face.

The aim of this Research Topic is to shed light on both known and unknown resistance mechanisms in NSCLC: impact on prognosis and therapeutic response; overlap of resistance mechanisms, new resistance mechanisms, testing methods, and therapeutic strategies.

Topics of interest include:

- Pre-treatment co-occurring alterations impacting on TKI response

- Liquid and solid biopsies in the definition of resistance mechanisms

- Tumor heterogeneity and response to TKIs

- Co-occurring resistance mechanisms

- Therapeutic strategies to overcome resistance mechanisms

Please note: Manuscripts consisting solely of bioinformatics, computational analysis, or predictions of public databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) will not be accepted in any of the sections of Frontiers in Oncology.

Keywords: Lung cancer, kinase inhibitors, primary resistance, acquired resistance, biomarkers, molecular tests, heterogeneity, co-occurring mutations

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