EML4-ALK fusion

A case of EML4-ALK fusion mutation in invasive lung adenocarcinoma has been reported. Multiple cystic changes occurred repeatedly in both kidneys, right rectus muscle, and psoas major muscle after treatment with crizotinib, and spontaneous absorption and resolution after discontinuation of the drug.

Combination treatment with lorlatinib and erlotinib significantly reduced HRG1-induced activation of RTK signaling in ALK-positive NSCLC cells. HER3 overexpression has potential as a prognostic marker in ALK-positive NSCLCs, including ALK-TKI naïve and treated cases, especially those with EML4-ALK V1/V2. Assessing HER3 expression may be crucial for treatment planning and outcome prediction in these patients.

Intriguingly, we also found that expression of Eg5-S1033D led to cells expressing EML4-ALK V1 adopting a more mesenchymal-like morphology. Taken together, we propose Eg5 acts as a substrate of NEK7 in cells expressing EML4-ALK V3 and that Eg5 phosphorylation promotes the altered morphology typical of these cells.

Both fluorouracil, leucovorin, and oxaliplatin (FOLFOX) and bevacizumab combined with 5-fluorouracil, l-leucovorin, and irinotecan (FOLFIRI) proved ineffective against the disease...The patient was initially treated with ensartinib monotherapy for 9 months, then with ensartinib combined with local radiotherapy and fruquintinib for another 4 months for isolated hilar hepatic lymph node metastasis. The patient experienced disease progression with an acquired ALK G1202R resistance mutation that responded well to lorlatinib...However, the patient responded remarkably well to alectinib. Our report emphasizes the importance of gene detection in the treatment of malignant tumors, and the significance of ALK mutations in CRC.

In this study, we systematically explored the validity of sequential ALK inhibitors (alectinib, lorlatinib, crizotinib, ceritinib and brigatinib) for a heavy-treated patient with EML4-ALK fusion via developing an in vitro and in vivo drug testing system based on patient-derived models. In summary, our results delineate clinical responses of sequential ALK-TKIs treatments and provide insights into the mechanisms underlying the superior effects of brigatinib in patients harboring ALKG1269A mutation and resistant towards alectinib, lorlatinib and crizotinib. The molecular signatures model based on the combination of IL6, CXCL1 and CXCL5 has the potential to predict prognosis of EML4-ALK positive NSCLC patients.

Furthermore, dEALK1 also exerts a potent antitumor activity against EML4-ALK-positive xenograft tumors without or with harboring ceritinib-resistant EML4-ALK mutations in vivo. Our study suggests that dEALK1-induced degradation of EML4-ALK fusion proteins is a promising therapeutic strategy for treatment of ALK-rearranged lung cancer with ceritinib resistance.

Consistently, mouse squamous tumors or LUAD with squamous signature display certain resistance to ALK inhibitor, which can be overcome by combined JAK1/2 inhibitor treatment. This study uncovers strong plasticity of ALK-rearranged tumors in orchestrating phenotypic transition and drug resistance and proposes a potentially effective therapeutic strategy.

These findings highlight the complexity of drug selection when treating patients harboring resistance mutations and suggest that the F1174S mutation in EML4-ALK variant 1 is likely not a potent oncogenic driver. Additional oncogenic driver or other resistance mechanisms should be considered in the case of EML4-ALK variant 1 with F1174S mutation.

This study affirms the efficacy of lorlatinib in patients with ALK-positive SCLC transformation harboring the V1180L mutation. Furthermore, it underscores the imperative of conducting genetic testing in patients who transition to SCLC following ALK-TKI resistance, as targeted therapies may remain efficacious if a genetic driver is identified.

Whole-transcriptome sequencing allowed the identification of actionable fusions with the potential to affect clinical decisions regarding therapy in 2.8% of RCC patient tumors. In addition, one patient was found to have a fusion that is characteristic of a solitary fibrous tumor, demonstrating the power of genomic profiling to aid diagnosis.

Conclusion  Oncogenic driver mutations are present in Indian NSCLC patients. Molecular testing should be performed for all patients of advanced NSCLC to identify those that can benefit from newer generation of targeted or immunotherapies.

ALK inhibitors first-line crizotinib, second-line ceritinib, and alectinib are effective against NSCLC patients with these rearrangements. Based on the Y1278-C1097 H-bond and E1167-K1150 salt bridge interaction, I1171N strongly promotes the constitutively active kinase independent of ATP. This structural mechanism study will aid in understanding the oncogenic activity of ALK and the basis for improving the ALK inhibitors.

By means of the diagnosis and treatment of this case, the characteristics and therapies of IMT are illustrated. In addition, it also provides a reference for the therapeutic strategy of IMT in the future.

Then, the patient received 1 cycle of chemotherapy with paclitaxel in combination with nedaplatin and subsequently received maintenance treatment involving lorlatinib. CONCLUSIONS This case demonstrates the potential advantage of lorlatinib as a neoadjuvant therapy in advanced ALK-positive NSCLC. It emphasizes the importance of identifying new therapeutic targets by next-generation sequencing (NGS) and implementing precise treatment strategies in clinical practice.

EML4-ALK fusion protein may enhance venous thrombogenicity by regulating coagulation factor TF expression. There was potential involvement of the pERK1/2-AP-1 pathway in this process.

Following corticosteroid treatment and discontinuation of alectinib, clinical presentations and CT scan gradually improved, but the primary lung lesions enlarged during the regular follow-up. The administration of crizotinib was then initiated and the disease was stable for 25 months without recurrence of primary lung lesions and ILD.

Multivariate Cox regression analysis revealed that harboring multiple ALK fusions had the potential to be an independent predictor of better PFS for ALK-positive NSCLC [hazard ratio (HR) =0.490; 95% confidence interval (CI): 0.229-1.049]. Harboring multiple ALK fusions could serve as an independent predictive marker of better clinical outcome for patients with NSCLC and ALK rearrangement who have received ALK-TKIs treatment.

No abstract available

Following corticosteroid treatment and discontinuation of alectinib, clinical presentations and CT scan gradually improved, but the primary lung lesions enlarged in the regular follow-up. The administration of a first-generation ALK inhibitor crizotinib was then initiated and the disease was stable for 25 months without recurrence of ILD.

Intrathyroid metastases require a high level of suspicion for diagnosis and tailored treatment based on primary tumour features, overall cancer burden and co-morbidities. This review provides a comprehensive update on the epidemiology, clinicopathological features and recent advancements in secondary thyroid cancer.

Brigatinib, a tyrosine kinase inhibitor (TKI) with specificity for gene rearranged anaplastic lymphoma kinase (ALK), such as the EML4-ALK, has shown a potential to inhibit mutated epidermal growth factor receptor (EGFR). The tumor-to-blood ratio in H2228 xenografts could be reduced by pretreatment with ALK inhibitor crizotinib. Tracer uptake in EGFR Del19 mutated HCC827 and EML4-ALK fusion A549 was not significantly different from uptake in A549 xenografts.

One expansion cohort of J-ALTA enrolled patients previously treated with ALK tyrosine kinase inhibitors (TKIs); the main cohort included patients with prior alectinib ± crizotinib. Exploratory analyses of baseline circulating tumor DNA in ALK TKI-pretreated NSCLC showed associations between poor PFS and EML4-ALK fusion variant 3 and TP53. Brigatinib is an important treatment option for Japanese patients with ALK+ NSCLC, including patients previously treated with alectinib.

NGS recommended an FDA-approved drug or clinical trial in 85.71% of cases; patients with only CTs available had the worst PFS; Our study provides results that suggest NGS may guide therapeutic decisions and potentially improve patient outcomes. Further research with larger sample sizes is needed to validate our findings and expand our understanding of the genomic landscape of lung cancer in Mexico.

Secondary rearrangement involving EML4-ALK which places the fusion gene under control of a new promoter may be a novel mechanism of resistance to crizotinib in IMT (and potentially other ALK-fusion-driven malignancies). Alectinib, a more potent ALK inhibitor, overcame resistance in this case. More broadly, this study exemplifies the importance of molecular testing in the setting of resistance to targeted therapy to inform clinical decision making.

Due to significant loculation, he was transferred to a tertiary center, underwent bronchoscopy however was a poor candidate for stenting/VATS, received oral salvage chemotherapy with Lorbrena...Next-generation ALK inhibitors like Alectinib and Brigatinib, have demonstrated clinical improvement and overall survival benefits in ALK-positive tumors when compared to chemotherapy... With this case, we emphasise the role of NGS, identification of EML4-ALK fusion in NSCLC and the potential role of tyrosine-kinase inhibitors in personalizing lung cancer therapy. Using combination therapy with ALK-TKIs and anti-PD1/PD-L1 antibodies in ALK positive NSCLC is an option that has not been sufficiently studied however is worth exploring in patients with resistant NSCLC [3].

To date, the detection of gene mutation using RNA from sputum samples is considered practically difficult. We report a case in which the EML4-ALK fusion gene was successfully detected from a sputum sample using the LCCP that was just released in Japan as a new next-generation sequencing lung cancer panel, CDx.

This trial is evaluating T-DXd alone or in combination with durvalumab (durva) or MEDI5752 (a PD-1/CTLA-4 bispecific antibody) with or without chemotherapy in pts with unresectable/metastatic, HER2-OE, nonsquamous NSCLC...In part 1 (enrollment completed), pts with disease progression after 1 or 2 lines of systemic therapy in the recurrent/metastatic setting receive T-DXd monotherapy or T-DXd + durva in combination with cisplatin, carboplatin, or pemetrexed...The primary endpoint is the frequency of adverse events (AEs) and serious AEs (SAEs) with T-DXd + durva + chemotherapy (part 1) or T-DXd + MEDI5752 ± chemotherapy (part 3). Secondary endpoints include confirmed objective response rate, duration of response, disease control rate, progression-free and overall survival, pharmacokinetics, and immunogenicity in all arms as well as the frequency of AEs and SAEs with T-DXd monotherapy (part 1).

Legal entity responsible for the study Fondazione Policlinico Universitario A Gemelli – IRCCS. In post-lorlatinib NGS-assay, 2 pts had ALK-compound mutations, while 4 pts had newly off-target alterations (CDKN2A/B CDKN2B loss, NF1 deletion, DNMT3A/ARID1A/CHECK2 M+). Conclusions Implementation of longitudinal genomic assessment is required in order to provide an extensive overview of resistance mechanisms and clinical outcomes according to current ALK-inhibitors treatment sequences.

This increase is likely to translate to a larger number of patients matched to and receiving targeted therapy. Consequently, RNA NGS should be considered for more widespread adoption in the clinic.

Conclusions CGP tests are being utilized in precision oncology, but NGS workflows and bioinformatics pipelines can be difficult to implement. The AVENIO CGP Tumor Tissue Kit is highly reproducible across sites and operators, achieving high sequencing quality metrics and diagnostic sensitivity.

Accordingly, the patient continued Osimertinib combined with Carboplatin/Pemetrexed and with additional palliative irradiation due to a new symptomatic spinal cord compression at L3. Acquired EML4-ALK fusion represents an extremely rare (1%) acquired mechanism of Osimertinib-resistance, which enables further effective and feasible therapy by combining EGFR- and ALK-TKI. Rebiopsies, when possible, are of noteworthy value even in heavily pretreated and fragile patients.

As lung adenocarcinoma patients significantly benefit from targeted therapy, the assessment of mutational profiles using NGS could become a crucial approach in the routine management of oncological patients.

The patient achieved a pathological complete response according to pathological evaluation. The patient received adjuvant crizotinib for 3 months and achieved a disease-free survival time of 36 months.

However, drug response results derived by CODRP were consistent with the actual clinical response. Conclusions We identified that CODRP prediction model using PDOs improves the accuracy of drug response prediction.; Public health; Endoscopy and interventional pulmonology; Cell and molecular biology; General respiratory patient care; Respiratory intensive care; Epidemiology; Surgery

She was started on Alectinib, but later switched to Lorlatinib due to concern for treatment failure in the setting of increased CEA levels. Therefore, it is crucial to identify skin lesions early and consider them as a potential manifestation of an internal malignancy.ConclusionSkin manifestations can be difficult to identify and can appear deceptively benign. Timely biopsy of suspicious lesions and further imaging should be performed to prevent delays in diagnosis and treatment.

Eltanexor showed a stronger effect than Selinexor potently inducing PARP cleavage. Consistently with in vitro data, we observed that selinexor impaired tumor growth in vivo, both in EML4-ALK transgenic mice and in ALK TKI-resistant xenograft tumors in mice.ConclusionThese data support the therapeutic value of SINEs alone or in combination with ALK-TKIs for the treatment of ALK+NSCLCs, even after their loss of responsiveness to targeted therapy and regardless of their p53 mutational status.

However, resistance to ALK inhibitors can occur via point-mutations within the kinase domain of the EML4-ALK fusion, e.g. G1202R, reducing inhibitor effectiveness. Here, we discuss the biology of EML4-ALK variants, their impact on treatment response, ALK-TKI drug resistance mechanisms, and potential combination therapies.

ZYY-B-2 could inhibit the expression of P-gp in a dose-dependent manner to overcome ceritinib resistance, and the suppression effect of ZYY-B-2 on P-gp might be related to its inhibition of PI3K/AKT signaling pathway. In summary, ZYY-B-2, a promising ALK inhibitor, shows potent activity against ceritinib-resistant cells, which provides experimental and theoretical basis for the further development of new ALK inhibitors.

Pts with advanced/metastatic NSCLC who were ALK+ in circulating tumor DNA by Guardant360 (G360) liquid biopsy test from Jan 1, 2018, to Dec 31, 2021, and received 1L monotherapy with a next-generation ALK TKI (alectinib, brigatinib, ceritinib, lorlatinib) were identified in the Guardant INFORM clinical-genomics database. Among pts with NSCLC and ALK fusion, co-occurrence of EML4-ALK V3 and TP53 mutation is common and associated with poor prognosis and high risk of early discontinuation of 1L treatment with a next-generation ALK TKI, most likely due to disease progression. Additional novel or combination therapies are warranted for this subpopulation. >a 117 pts had data for both TP53 and EML4-ALK V1 or V3.

In addition, chemotherapy combined with immunotherapy subsequently achieved a survival benefit of more than 25 months. Therefore, alectinib may be a viable therapeutic option for NSCLC patients with double ALK fusion and immunotherapy combined with chemotherapy may be a viable therapeutic option when double ALK fusion loss may be the mechanism of alectinib resistance.