SDC4-ROS1 fusion

This study confirmed that OA could inhibit SDC4 expression and promote the occurrence of ferroptosis in A549 cells and H1299 cells through the GPX4/ACSL4 pathway, providing an effective basis for the use of drugs targeting ferroptosis in lung cancer treatment.

The Ki67 index was not different, but ROS1 and pERK1/2 expression levels tended to be higher in the tumor cells of case 2 than in case 1. Therapeutic response to crizotinib and patients' prognosis in ROS1 rearranged NSCLC may be related to the activation of ROS1 signaling, depending on ROS1 and pERK1/2 overexpression status, even if the ROS1 fusion partner is the same.

Long CD74/SLC34A2-ROS1 fusions, which retain transmembrane regions in ROS1 and fusion partners, are associated with poor response to crizotinib independent of TP53 mutations.

"Gene fusions represent crucial targets in the context of precision medicine. NGS testing for fusion detection not only allows analysis of multiple targets but also saves time and material. The identification of novel fusions in this study also highlights the potential for future therapeutic targets."

According to the molecular dynamics simulation results, ROS1 L2010M mutations (happening in the ROS1 kinase ATP binding cassette) maybe resistant to lorlatinib, entrectinib, cabozantinib, and crizotinib... In summary, CD74- and SLC34A2-ROS1 patients showed better crizotinib efficacy with different resistance mutation patterns. Patients of these subtypes are potential beneficiaries of molecular testing after crizotinib progression, directing future treatment strategies. Multiple TKI treatments may lead to the accumulation of both on-target and off-target resistance mutations.

This study describes 14 novel ROS1 fusion partners based on the largest ROS1 fusion cohort, and the ROS1 breakpoint was mostly located between exons 32 and 34. Additionally, next-generation sequencing is an optional method for identifying novel ROS1 fusions.

On the contrary, the treatment with other TKIs, such as lorlatinib, entrectinib and DS-6051b, did not result in cell growth inhibition. In addition, ADK-VR2 tumor growth was significantly reduced but not eradicated by crizotinib treatment. The ADK-VR2 cell line is a promising NSCLC preclinical model for the study of novel targeted therapies against ROS1 fusions and the mechanisms of resistance to TKI therapies.

Concurrent driver oncogenes mutation with ROS1 rearrangement defines a unique subgroup of NSCLC. Patients with concomitant ROS1 rearrangement might have a better prognosis.

Background Based on the approvals of crizotinib and entrectinib by the Food and Drug Administration for the treatment of ROS1-positive non-small lung cancer, we sought to analysis of ROS1 fusions characteristics in Chinese solid tumor patients to explore the possibility of therapeutic intervention in solid tumors. ROS1 fusion is an important driver genomic alteration in both the lung cancer and non-lung cancer cohorts. ROS1 targeted therapies should be further explored in non-lung cancer in clinical studies.

On the contrary, the treatment with other TKIs, such as entrectinib and DS-6051b, did not result in cell growth inhibition. Lorlatinib showed dramatically different efficacy, depending on the cell culture conditions...Additionally, the crizotinib-resistant clone ADK-VR2 AG143 showed a slower growth in vivo, compared to ADK-VR2; suggesting a role for crizotinib in modulation of stemness and growth. Conclusion The ADK-VR2 cell line is a promising NSCLC preclinical model for the study of novel targeted therapies against ROS1 fusions and the mechanisms of resistance to TKI therapies.

In summary, we established brain metastases lung cancer PDX models as reliable platforms for interrogation of targets and kinetics related mechanism and for drug screening. The use of such techniques will increase our knowledge of the metastatic process and help identify new targets of cancer metastasis.

Crizotinib and entrectinib are FDA-approved ROS1 tyrosine kinase inhibitors (TKIs), but clinical emergence of ROS1 resistance mutations S1986F/Y, F2004C/I/V, L2026M, G2032R, and D2033N restricts their therapeutic utility...TRKB inhibition in the central nervous system has been implicated in adverse events observed with FDA-approved dual TRK/ROS1 inhibitor entrectinib and FDA-approved ALK inhibitor lorlatinib...In conclusion, the preclinical profile of NVL-520 supports its potential to address a medical need for patients with a diverse array of ROS1 fusion partners and kinase-domain mutations, both in NSCLC and in other cancers such as glioblastoma. NVL-520 is being evaluated in a Phase 1/2 clinical trial for patients with advanced ROS1-positive NSCLC or other solid tumors (NCT05118789).

Conclusion The relationship between the different ROS1 fusion variant and the clinical courses including crizotinib sensitivity is still unclear. It was suggested, however, that the differences of ROS1 fusion variants may correlate with the activity level of ROS1 signal transduction ,depending on ROS1 overexpression status, and aggressive tumor behavior.

The patient received crizotinib therapy and was considered to have a partial response...Conclusion To our knowledge, SDC4-ROS1 fusion gene as a novel mechanism of acquired EGFR resistance in lung adenocarcinoma is the first reported in China. In the future, the routine use of next generation sequencing is important, more and more ROS1 fusions are identified in lung cancer by next generation sequencing.

Conclusion ROS1 fusions were found in 1.5% of Chinese NSCLC patients, which occurred more frequently in younger patients, female and never-smokers. NGS is a reliable technique to assess ROS1 fusions, including both classic and rare ROS1 fusions.

Uncommon ALK/ROS1/RET genomic breakpoint is an unreliable predictor of matched targeted therapy efficacy. Functional validation by RNA or protein assay may add value for accurate detection and interpretation of rare fusions.

In addition, SAF-189s was more potent than crizotinib and comparable to lorlatinib, the most advanced ROS1i known against the ROS1. Collectively, these results suggest the promising potential of SAF-189s for the treatment of patients with the ROS1 fusion G2032R mutation who relapse on crizotinib. It is now recruiting both crizotinib-relapsed and naive ROS1-positive NSCLC patients in a multicenter phase II trial (ClinicalTrials.gov Identifier: NCT04237805).

The tyrosine kinase inhibitors (TKIs), crizotinib, lorlatinib, and entrectinib have demonstrated favorable efficacy in treating ROS1-rearranged NSCLCs. ROS1 mutations, including G2032R were observed in approximately 33% of post-crizotinib samples. Collectively, we report the prevalence of ROS1 fusions in a large-scale NSCLC population, and the efficacy of crizotinib in treating patients with ROS1-rearranged NSCLC.

Legal entity responsible for the study: Depei Huang. Funding: Has not received any funding.

More than 30 different fusion partner genes of ROS1 in NSCLC have been reported and most of these ROS1 fusions respond well to crizotinib, entrectinib, ceritinib and lorlatinib. Legal entity responsible for the study: The authors. Funding: Has not received any funding.

No abstract available

The tyrosine kinase inhibitors (TKIs) including crizotinib, lorlatinib, and entrectinib, have demonstrated favorable efficacy in the treatment of ROS1-rearranged NSCLCs.Methods A total of 17,158 Chinese non-small cell lung cancer (NSCLC) patients whose tumor specimen and/or circulating cell-free DNA (cfDNA) underwent genomic profiling by hybridization capture-based targeted NGS of exons and introns of cancer related genes were retrospectively reviewed. In addition, two out of three patients who had uncharacterized fusion partners (IGR-ROS1) achieved durable clinical benefit on crizotinib.Conclusion We hereby report the prevalence of ROS1 fusions of 1.7% in a large Chinses NSCLC population detected by NGS testing and the most frequent fusion partners including CD74, EZR, SDC4, and SLC34A2. Crizotinib has demonstrated robust response in treating ROS1-rearranged NSCLC, particularly in non-CD74 ROS1-positive patients.

Drugs targeting tyrosine kinases TrkA/B/C and ROS1, such as larotrectinib and entrectinib, are proven highly efficacious in diverse adult and pediatric tumor types (ORR > 75%)...The use of second generation of TKI, such as repotrectinib to against these acquired resistance mutations, has been explored in clinical trials and reported unsatisfied efficacy in patients under acceptable dosages, which might due to its broader inhibition of multiple kinases... Collectively, these studies have shown SIM1803-1A is a potent Trk/ROS1 dual inhibitor with better safety potentially from improved kinase selectivity. SIM1803-1A is currently at IND submission stage and represents a promising clinical candidate for the treatment-naïve and acquired-resistance NTRK/ROS1 fusion-positive malignancies. Research Funding: None