Herein, we provide a comprehensive overview on the therapeutic strategies for overcoming acquired resistance to tyrosine kinase inhibitors (TKIs) targeting the most well-established oncogenic gene fusions in advanced NSCLC, including ALK, ROS1, RET, and NTRK rearrangements.Targeted therapy has become the standard of care for non-small cell lung cancers with a range of targetable alterations, including ALK and ROS1 kinase fusions. RET fusions drive the oncogenesis of 1-2% of NSCLCs and represent a substantial global burden of disease. Although these fusions were first identified more than thirty years ago, targeted therapy for RET fusion-positive lung cancers was only explored in the last decade. Whereas repurposed multikinase inhibitors were initially tested, selective inhibitors RET inhibitors have dramatically improved outcomes for patients whose tumors harbor these alterations. In 2020, the US Food and Drug Administration approved selpercatinib, a selective RET inhibitor, for adults with lung and thyroid cancers with RET rearrangements or mutations, making it the first targeted therapy to be approved for RET-altered cancers. While resistance to selective RET inhibition has been described, next-generation RET inhibitors are already being explored for patients who progress on prior RET kinase inhibitors.Several subsets of non-small cell lung cancer (NSCLC) are defined by the presence of oncogenic rearrangements that result in constitutive activation of a chimeric fusion protein. In NSCLCs that harbor ALK or ROS1 rearrangements, aberrant signaling from these fusion proteins can be overcome by potent and selective tyrosine kinase inhibitors (TKIs). These targeted therapies can induce durable responses and significantly improve prognostic outcomes. Historically, analysis of tissue biopsies was the primary approach to identifying key activating rearrangements. In recent years, non-invasive genotyping of tumor-derived nucleic acids in the circulation has gained ground as a strategy for determining the genetic composition of NSCLCs at diagnosis and throughout the disease course based on prospective and retrospective studies validating the utility of plasma analysis in heterogeneous populations of patients with metastatic NSCLC. Notably, these practice-changing studies predominantly included patients with NSCLCs with oncogenic mutations. Compared to other types of molecular alterations such as mutations and insertions/deletions, oncogenic rearrangements are more complex as they incorporate a variety of fusion partners and diverse breakpoints. Because of this structural complexity, detecting oncogenic rearrangements with plasma assays is more challenging than identifying disease-defining point mutations. In this review, we discuss technical aspects of plasma genotyping strategies and summarize findings from studies exploring plasma genotyping (including ctDNA analysis and profiling of nucleic acids contained in other plasma components) in two rearrangement-driven NSCLC subsets (ALK-rearranged and ROS1-rearranged).Anaplastic lymphoma kinase (ALK) translocations are responsible of neoplastic transformation in a limited subset of non-small cell lung cancer (NSCLC) patients. In recent years outcomes of these patients improved due to the development and clinical availability of specific and extremely active targeted therapies [i.e., next-generation Tyrosine Kinase Inhibitors (TKI)] ALK+ patients are now reaching impressive results when treated with more potent inhibitors upfront with an average median progression-free survival (mPFS) around 35 months. However, under drug pressure, cancer cells develop resistance and patients eventually progress.  https://www.selleckchem.com/products/nvp-bgt226.html  Multiple mechanisms of intrinsic or acquired resistance have been extensively characterized. Less potent ALK inhibitors (ALKi)-like crizotinib-usually tend to induce a large spectrum of secondary intra-kinase mutations; however, these alterations may be observed also after sequential administration of multiple ALKi. Noteworthy, neoplastic cells may evade ALK targeting through a myrgeted treatment for these patients.The tropomyosin receptor kinase (TRK) family of receptor tyrosine kinases has become a focus of clinical interest because the NTRK genes (NTRK1-3) encoding them have been identified as oncogenic fusion genes in a wide range of different tumor types, including lung cancer. These NTRK gene fusions usually occur at a low frequency below 1%, in non-small cell lung cancer (NSCLC) in 0.1-0.2% of the cases and have been reported across a wide range of tumor types. The TRK fusion proteins encoded by such gene fusions have constitutively activated tyrosine kinase domains and constitute actionable targets for tyrosine kinase inhibitors (TKIs). The first generation TRK TKIs larotrectinib and entrectinib have been investigated in clinical phase I and II trials in solid tumors both in adult and pediatric patients and results have demonstrated high response rates that are durable and with generally good tolerability. This has led to approval of these TRK inhibitors by regulatory authorities in the USA, Europe and Japan as tumor agnostic treatment of advanced or recurrent NTRK fusion-positive cancers in adult and pediatric patients. With a focus on lung cancer, this review gives a background to NTRK fusion genes, presents clinical data for TRK inhibitors and discuss the issue of acquired resistance to TRK inhibition.Anaplastic lymphoma kinase (ALK) inhibitors have demonstrated robust clinical activity in patients with ALK-rearranged lung cancers. The echinoderm microtubule-associated protein-like (EML)-ALK translocation was first discovered in 2007 and 4 years later, crizotinib, a first-generation ALK inhibitor was approved. Since then, subsequent generations of ALK inhibitors have demonstrated superior efficacy and better CNS activity compared to crizotinib. Alectinib and brigatinib, both second-generation ALK inhibitors have been compared directly to crizotinib in the first-line setting and has demonstrated improved progression free survival (PFS) and intracranial response. Ceritinib, another second-generation ALK inhibitor has been shown to be superior to chemotherapy in ALK-rearranged disease with good CNS activity. Initial responses to ALK inhibitors are not always durable and resistance can occur as on-target or off-target alterations. Lorlatinib, a third-generation ALK inhibitor, has demonstrated activity in the treatment naïve setting and in resistance to crizotinib and second-generation ALK inhibitors.