"Here we present a case of a patient with stage IV CD-74-ROS1 fusion NSCLC discovered initially with RNA next generation sequencing (NGS) who acquired resistance to lorlatinib after 6 months on therapy through a novel RUFY1-RET fusion, detected only through RNA NGS."
BUFFALO, NY - February 6, 2025 – A new case report was published in Volume 16 of Oncotarget on February 5, 2025, titled " Acquired RUFY1-RET rearrangement as a mechanism of resistance to lorlatinib in a patient with CD74-ROS1 rearranged non-small cell lung cancer: A case report ."
In this case report, Jenny L. Wu from Vanderbilt University School of Medicine and Wade T. Iams from Vanderbilt-Ingram Cancer Center describe a rare case of drug resistance in a patient with advanced non-small cell lung cancer (NSCLC). The patient, a 42-year-old man who had never smoked, initially responded well to lorlatinib, a targeted therapy designed to treat cancer driven by specific genetic alterations. However, after six months, his cancer began to grow again. Clinicians discovered that this was due to a new genetic change, known as the RUFY1-RET fusion. This finding highlights how cancers can adapt to treatment and the importance of ongoing genetic testing to guide therapy decisions.
NSCLC is the most common type of lung cancer, and in some cases, it is driven by genetic changes that can be targeted with specific drugs. The patient's cancer originally had a ROS1 gene rearrangement, which made it responsive to lorlatinib. But as time went on, the cancer started to grow again, and tests revealed a new genetic alteration called RUFY1-RET fusion, which likely caused resistance to lorlatinib.
This new genetic change was identified using RNA next-generation sequencing (RNA NGS), an advanced test that can find mutations that standard genetic tests might miss. After discovering the RUFY1-RET gene fusion, the patient was treated with a combination of lorlatinib and pralsetinib, a drug that specifically targets RET gene alterations. While this combination helped control the cancer for about four months, the patient's condition unfortunately worsened after four months.
"This is the first reported case of a RET fusion as a potential mechanism of resistance to lorlatinib, it identifies a novel RET fusion partner, and it emphasizes the importance of testing for acquired resistance mutations with both DNA and RNA at the time of progression in patients with targetable oncogenic drivers."
Understanding cases like this can help clinicians and researchers develop more effective treatment strategies, including combination therapies that target multiple genetic changes to combat drug resistance. While the combined therapy in this case provided only temporary benefits, it offers important insights for future research and patient care, particularly for cancers that no longer respond to standard treatments.
Continue reading: DOI: https://doi.org/10.18632/oncotarget.28682
