Transcriptomics-Guided Personalized Prescription of Targeted Therapeutics for Metastatic ALK-Positive Lung Cancer Case Following Recurrence on ALK Inhibitors

Abstract

Non-small cell lung carcinoma (NSCLC) is the major cause of cancer-associated mortality. Identification of rearrangements in anaplastic lymphoma kinase (ALK) gene is an effective instrument for more effective targeted therapy of NSCLC using ALK inhibitors dramatically raising progression-free survival in the ALK-mutated group of patients. However, the tumors frequently develop resistance to ALK inhibitors. We describe here a case of 48 y.o. male patient with ALK-positive NSCLC who was clinically managed for 6.5 years from the diagnosis. The tumor was surgically resected, but 8 months later multiple brain metastases were discovered. The patient started receiving platinum-based chemotherapy and then was enrolled in a clinical trial of second-generation ALK inhibitor ceritinib, which resulted in a 21 months stabilization. Following disease relapse, the patient was successfully managed for 33 months with different lines of chemo- and local ablative therapies. Chemotherapy regimens, including off-label combination of crizotinib + bevacizumab + docetaxel, were selected using the cancer transcriptome data-guided bioinformatical decision support system Oncobox. These therapies led to additional stabilization for 22 months. Survival of our patient after developing resistance to ALK inhibitor was longer for 16 months than previously reported average survival for such cases. This case shows that transcriptomic-guided sequential personalized prescription of targeted therapies can be effective in terms of survival and quality of life in ALK-mutated NSCLC.

Algorithmic Annotation of Functional Roles for Components of 3,044 Human Molecular Pathways

“…The ARR-annotated pathways can be used for further calculations of PALs using high-throughput gene expression data, e.g., RNA sequencing or proteomic profiles ( Buzdin et al, 2018 ; Figure 2 ). To this end, several previously published bioinformatic methods can be employed ( Buzdin et al, 2014a ; Ozerov et al, 2016 ; Borisov et al, 2020 ), and the PAL values returned can be applied for a variety of applications including fundamental research ( Pasteuning-Vuhman et al, 2017 ), drug development ( Aliper et al, 2017a ; Ravi et al, 2018 ; Bakula et al, 2019 ), and personalized medicine ( Poddubskaya et al, 2019a ; Moisseev et al, 2020 ). Technically, PAL values can be used as the next-generation molecular biomarkers ( Aliper et al, 2017b ; Borisov et al, 2017 ; Sorokin et al, 2020c ) or as the substrates for various machine learning applications ( Borisov et al, 2018 ; Tkachev et al, 2018 ).…”

“…A number of PALs were found to be characteristic for cancer drug response ( Zhu et al, 2015 ) and sensitivity to X-ray irradiation ( Sorokin et al, 2018 ), asthma ( Alexandrova et al, 2016 ), Hutchinson-Gilford progeria ( Aliper et al, 2015 ), macular degeneration ( Makarev et al, 2014 ), fibrosis ( Makarev et al, 2016 ), viral infection ( Buzdin et al, 2016 ), and aging ( Aliper et al, 2016 ). Algorithms were developed to convert pathway activation data into the optimized selection of cancer drugs ( Artemov et al, 2015 ; Tkachev et al, 2020 ) that had several recent clinical applications ( Poddubskaya et al, 2018 , 2019a , b ; Sorokin et al, 2020b ). However, those studies used manually curated/annotated pathways and were, therefore, limited by the overall number (~10 or ~100) of pathways under analysis.…”

Disparity between Inter-Patient Molecular Heterogeneity and Repertoires of Target Drugs Used for Different Types of Cancer in Clinical Oncology

“…However, further accumulation of clinically annotated high throughput molecular profiles, for example, References [71][72][73] can dramatically improve this situation in the future.…”

The Potential of OMICs Technologies for the Treatment of Immune-Mediated Inflammatory Diseases

“…Kim et al, recently described the successful use of tofacitinib in a patient with drug-induced hypersensitivity syndrome after performing an scRNAseq analysis of the patient’s skin and blood [ 23 ]. ScRNAseq has also been successfully used in other cases such as metastatic ALK-positive lung cancer [ 24 ]. Costs of sequencing applications have decreased significantly over the last 20 years.…”