Non-small cell lung cancer (NSCLC) constitutes 85% of lung cancer cases and represents a leading cause of cancer-related mortality globally. This significant prevalence underscores the importance of understanding the diverse molecular alterations associated with NSCLC. Gene fusions represent a specific type of molecular alteration resulting from chromosomal rearrangements or splicing errors during transcription. While anaplastic lymphoma kinase (ALK) rearrangements have been extensively studied, the post-progression management of patients with other gene fusions, such as ROS proto-oncogene 1 (ROS1), rearranged during transfection proto-oncogene (RET), or neurotrophic tyrosine receptor kinase (NTRK) remains an active research area. Resistance and subsequent disease progression necessitate thoroughly examining potential resistance mechanisms to develop targeted therapeutic interventions. Resistance to treatments targeting ROS1, RET, or NTRK fusions can arise from intrinsic and extrinsic alterations to these genes. In response to these different resistance mechanisms, specific therapies are being studied, such as the combination of tyrosine kinase inhibitors (TKIs) or novel molecular-targeted therapies. This review aims to evaluate the current understanding of genetic and non-genetic resistance mechanisms to TKIs in NSCLC with non-ALK gene fusions. Additionally, we highlight recently identified gene fusions and discuss their potential implications for future clinical practice, emphasizing the need for ongoing research to improve patient outcomes in this challenging and dynamic field of oncology.
Genetic and non-genetic resistance mechanisms in non-small cell lung cancer harboring (non-ALK) oncogenic fusions
Sposito, Marco;Scaglione, Ilaria Mariangela;Dodi, Alessandra;Avancini, Alice;Trestini, Ilaria;Insolda, Jessica;Milella, Michele;Pilotto, Sara;Belluomini, Lorenzo
2024-01-01
Abstract
Non-small cell lung cancer (NSCLC) constitutes 85% of lung cancer cases and represents a leading cause of cancer-related mortality globally. This significant prevalence underscores the importance of understanding the diverse molecular alterations associated with NSCLC. Gene fusions represent a specific type of molecular alteration resulting from chromosomal rearrangements or splicing errors during transcription. While anaplastic lymphoma kinase (ALK) rearrangements have been extensively studied, the post-progression management of patients with other gene fusions, such as ROS proto-oncogene 1 (ROS1), rearranged during transfection proto-oncogene (RET), or neurotrophic tyrosine receptor kinase (NTRK) remains an active research area. Resistance and subsequent disease progression necessitate thoroughly examining potential resistance mechanisms to develop targeted therapeutic interventions. Resistance to treatments targeting ROS1, RET, or NTRK fusions can arise from intrinsic and extrinsic alterations to these genes. In response to these different resistance mechanisms, specific therapies are being studied, such as the combination of tyrosine kinase inhibitors (TKIs) or novel molecular-targeted therapies. This review aims to evaluate the current understanding of genetic and non-genetic resistance mechanisms to TKIs in NSCLC with non-ALK gene fusions. Additionally, we highlight recently identified gene fusions and discuss their potential implications for future clinical practice, emphasizing the need for ongoing research to improve patient outcomes in this challenging and dynamic field of oncology.
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