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|Ref Type||Journal Article|
|Authors||Zhou Y, Jiang W, Zeng L, Mi J, Song L, Lizaso A, Mao X, Yang N, Zhang Y|
|Title||A novel ROS1 G2032 K missense mutation mediates lorlatinib resistance in a patient with ROS1-rearranged lung adenocarcinoma but responds to nab-paclitaxel plus pembrolizumab.|
|Journal||Lung cancer (Amsterdam, Netherlands)|
|Date||2020 Mar 19|
|Abstract Text||ROS1-rearranged non-small cell lung cancer (NSCLC) has demonstrated promising response to lorlatinib; however, no targeted therapy is available after failure of lorlatinib and information on acquired resistance mechanisms mediating lorlatinib resistance among ROS1-rearranged NSCLC patients is limited. We report a ROS1-rearranged NSCLC patient who responded to immunochemotherapy after acquisition of ROS1 G2032K-mediated lorlatinib resistance.Next-generation sequencing (NGS) was performed on supraclavicular lymph nodes (SLN) and blood samples obtained from the 53-year old male patient with advanced CD74-ROS1-rearranged NSCLC. In vitro experiments with patient-derived SLN tumor cells and in silico homology modeling were performed to investigate mechanisms of G2032K-mediated inhibitor resistance.NGS analysis revealed the detection of an acquired ROS1 G2032 K after failure from lorlatinib. Homology modeling revealed the conformational change in the inhibitor binding site induced by the ROS1 G2032 K that disrupted lorlatinib binding. In vitro experiments using patient-derived cells bearing concurrent CD74-ROS1-rearrangement and ROS1 G2032 K demonstrated half-maximal inhibitory concentration IC50 of 730.2 nM for lorlatinib, 812.1 nM for entrectinib, and 1546 nM for crizotinib, indicating resistance to these inhibitors. With PD-L1 expression of TPS 30 %, nab-paclitaxel plus pembrolizumab was administered as fifth-line treatment and achieved partial response, with sustained response ongoing for 7 months as of January 31, 2020.ROS1 G2032 K is a novel mutation that mediates resistance to lorlatinib. With the lack of targeted therapeutic options after lorlatinib resistance, checkpoint inhibitor plus chemotherapy may be considered as a treatment option in patients with ROS1-rearranged NSCLC.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|ROS1||G2032K||missense||unknown||ROS1 G2032K lies within the protein kinase domain of the Ros1 protein (UniProt.org). G2032K has been associated with secondary drug resistance (PMID: 32208297), but has not been biochemically characterized and therefore, its effect on Ros1 protein function is unknown (PubMed, Nov 2022).||Y|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|CD274 positive||lung adenocarcinoma||predicted - sensitive||Nab-paclitaxel + Pembrolizumab||Case Reports/Case Series||Actionable||In a clinical case study, a lung adenocarcinoma patient with CD274 (PD-L1) expression of 30% and harboring CD74-ROS1 and ROS1 G2032K demonstrated a partial response after being treated with the combination therapy of Keytruda (pembrolizumab) and Abraxane (nab-paclitaxel) for two cycles (PMID: 32208297).||32208297|