Abstract
Simple SummaryThe use of tyrosine kinase inhibitors has significantly improved the outcome of patients with ALK (anaplastic lymphoma kinase)-rearranged non-small cell lung cancer. Combining drugs with radiotherapy could increase its effectiveness on tumors or overcome resistance to ALK-targeted therapies. In this review, we provide a clinical and preclinical overview of combining radiation therapy with ALK inhibitors in anaplastic lymphoma kinase-positive non-small cell lung cancer, and we also propose several approaches to overcome resistance to ALK-targeted therapies with a combination of radiation and tyrosine kinase inhibitors.Over the past years, the identification of genetic alterations in oncogenic drivers in non-small cell lung cancer (NSCLC) has significantly and favorably transformed the outcome of patients who can benefit from targeted therapies such as tyrosine kinase inhibitors. Among these genetic alterations, anaplastic lymphoma kinase (ALK) rearrangements were discovered in 2007 and are present in 3–5% of patients with NSCLC. In addition, radiotherapy remains one of the cornerstones of NSCLC treatment. Moreover, improvements in the field of radiotherapy with the use of hypofractionated or ablative stereotactic radiotherapy have led to a better outcome for localized or oligometastatic NSCLC. To date, the effects of the combination of ALK inhibitors and radiotherapy are unclear in terms of safety and efficacy but could potently improve treatment. In this manuscript, we provide a clinical and preclinical overview of combining radiation therapy with ALK inhibitors in anaplastic lymphoma kinase-positive non-small cell lung cancer.
Highlights
Introduction published maps and institutional affilThe management of non-small cell lung cancer (NSCLC) has become challenging in recent years with the development and efficacy of new therapies such as immunotherapy and the identification of genetic alterations in oncogenic drivers susceptible to targeted therapies, such as tyrosine kinase inhibitors (TKIs)
Several randomized phase III trials have demonstrated improved efficiency using epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitors with regard to cytotoxic chemotherapies such as platinum agents combined with pemetrexed or docetaxel, indicating that targeted therapies should be the standard care for some selected patients [1,2,3,4]
Improvements in the field of radiotherapy have led to better outcomes for localized, advanced or oligometastatic NSCLC, with the use of intensity-modulated radiation therapy (IMRT), hypofractionated or ablative stereotactic radiotherapy (SBRT) and image-guided and adaptive radiotherapy [5,6,7,8]
Summary
The echinoderm microtubule-associated protein-like 4-anaplastic lymNSCLC [12,13]. The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene, resulting from an inversion within chromosome phoma kinase (EML4-ALK) fusion gene, resulting from an inversion within chromosome. ALK rearrangements are significantly correlated with PI3K (phosphatidylinositol 3-kinase)/AKT/mTOR (mammalian target of rapamycin) and RAS (rat sarcoma)/RAF/MEK (mitogen-activated protein kinase or Erk kinase) signaling pathways, leading to cell survival, proliferation and growth differentiation and translation [14]. In this molecular subgroup of NSCLC, ALK rearrangements critically confer sensitivity to ALK inhibition. Patients with ALK rearrangements are younger than those without ALK rearrangements, and most patients have little or no exposure to tobacco and present predominantly adenocarcinomas [12]
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