Pharmacotherapeutic advances with anaplastic lymphoma kinase inhibitors for the treatment of non-small cell lung cancer

Indini, Alice; Rijavec, Erika; Ghidini, Michele; Bareggi, Claudia; Gambini, Donatella; Galassi, Barbara; Antonelli, Paola; Bettio, Giulia; Nubila, Clarissa Di; Grossi, Francesco

doi:10.1080/14656566.2020.1738387

Cited by 7 publications

(3 citation statements)

References 56 publications

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“…Second, several studies have revealed that the efficacy of second-/third-generation ALK TKIs, including alectinib, brigatinib, ensartinib, and lorlatinib, is superior to that of crizotinib as first-line treatment in recent years. [43][44][45][46] Thus, comparing the clinical outcome mainly on the basis of crizotinib may be limited. Third, although we found that the characteristics of genomic breakpoints in uncommon ROS1 and RET fusions were similar to those in uncommon ALK fusions, their clinical relevance with targeted therapy was not evaluated owing to the relatively small sample size.…”

Section: Discussionmentioning

confidence: 99%

Potential Unreliability of Uncommon ALK, ROS1, and RET Genomic Breakpoints in Predicting the Efficacy of Targeted Therapy in NSCLC

Guo

Liu

et al. 2021

Journal of Thoracic Oncology

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Introduction: Variable genomic breakpoints have been identified through the application of target-capture DNA next-generation sequencing (NGS) for ALK, ROS1, and RET fusion detection in NSCLC. We investigated whether ALK, ROS1, and RET genomic breakpoint location can predict matched targeted therapy efficacy.Methods: NSCLCs were analyzed by DNA NGS, targetspecific RNA NGS, whole-transcriptome sequencing, and immunohistochemistry.Results: In total, 3787 NSCLC samples were analyzed. DNA NGS detected ALK, ROS1, and RET fusions in 241, 59, and 76 cases, respectively. These fusions were divided into canonical (single EML4-ALK, CD74/EZR/TPM3/SDC4-ROS1, and KIF5B/CCDC6-RET fusions), noncanonical (single non-EML4-ALK, non-CD74/EZR/TPM3/SDC4-ROS1, and non-KIF5B/CCDC6-RET fusions), and primary/reciprocal (both primary and reciprocal rearrangements were detected) subtypes on the basis of genomic breakpoint position, and noncanonical and primary/reciprocal subtypes were defined as uncommon fusions. Further RNA sequencing and immunohistochemistry revealed that six of 47 (12.8%) uncommon fusions were actually nonproductive rearrangements that generated no aberrant transcripts or proteins. Moreover, genomic breakpoints of canonical ALK and RET, but not ROS1, fusions always predicted breakpoints at the transcript level, whereas 85.4% (35 of 41) of uncommon fusions actually produced canonical fusion transcripts. Patients with uncommon ALK fusion (n ¼ 31) who received first-line crizotinib exhibited shorter median progressionfree survival than those with canonical ALK fusion (n ¼ 53, 8.4 mo versus 12.0 mo, p ¼ 0.004). However, no difference in progression-free survival was observed when only ALK RNA or protein-positive cases were analyzed (p ¼ 0.185).Conclusions: Uncommon ALK, ROS1, and RET genomic breakpoint is an unreliable predictor of matched targeted therapy efficacy. Functional validation by RNA or protein assay may add value for the accurate detection and interpretation of rare fusions.

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Section: Discussionmentioning

confidence: 99%

Potential Unreliability of Uncommon ALK, ROS1, and RET Genomic Breakpoints in Predicting the Efficacy of Targeted Therapy in NSCLC

Guo

Liu

et al. 2021

Journal of Thoracic Oncology

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“…Several ROS inhibitors that have been developed are mainly tested for adult patients with NSCLC (64). Currently, three are being evaluated for children; ensartinib, entrectinib and repotrectinib (clinical open trials: Ensartinib NCT03213652 phase II, Entrectinib NCT02650401phase I/II, Repotrectinib NCT04094610 phase I/II) (29,60,(65)(66)(67)(68). Hopefully these trials will lead to ROS-inhibitors approved for clinical use for children with brain tumors and could help the current patient in case of relapse.…”

Section: Discussionmentioning

confidence: 99%

NovelTPR::ROS1Fusion Gene Activates MAPK, PI3K and JAK/STAT Signaling in an Infant-type Pediatric Glioma

Deland

Keane

Bontell

et al. 2022

Cancer Genomics Proteomics

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Background/Aim: Although fusion genes involving the proto-oncogene receptor tyrosine kinase ROS1 are rare in pediatric glioma, targeted therapies with small inhibitors are increasingly being approved for histology-agnostic fusionpositive solid tumors. Patient and Methods: Here, we present a 16-month-old boy, with a brain tumor in the third ventricle. The patient underwent complete resection but relapsed two years after diagnosis and underwent a second operation. The tumor was initially classified as a low-grade glioma (WHO grade 2); however, methylation profiling suggested the newly WHO-recognized type: infant-type hemispheric glioma. To further refine the molecular background, and search for druggable targets, whole genome (WGS) and whole transcriptome (RNA-Seq) sequencing was performed. Results: Concomitant WGS and RNA-Seq analysis revealed several segmental gains and losses resulting in complex structural rearrangements and fusion genes. Among the top-candidates was a novel TPR::ROS1 fusion, for which only the 3' end of ROS1 was expressed in tumor tissue, indicating that wild type ROS1 is not normally expressed in the tissue of origin. Functional analysis by Western blot on protein lysates from transiently transfected HEK293 cells showed the TPR::ROS1 fusion gene to activate the MAPK-, PI3K-and JAK/STAT-pathways through increased phosphorylation of ERK, AKT, STAT and S6. The downstream pathway activation was also confirmed by immunohistochemistry on tumor tissue slides from the patient. Conclusion: We have mapped the activated oncogenic pathways of a novel ROS1-fusion gene and broadened the knowledge of the newly recognized infant-type glioma subtype. The finding facilitates suitable targeted therapies for the patient in case of relapse.The most common solid malignancies of childhood are tumors of the central nervous system (CNS). Glioma comprises the largest group of CNS tumors among these patients (40-50%), 711

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“…ALK is mainly expressed in adult brain tissue and plays an essential role in the function of central and peripheral nervous systems ( Golding et al, 2018 ). Accumulating evidence indicates that gene amplification in the ALK domain or the acquisition of activating point mutations have been found in neuroblastoma, anaplastic large cell non-Hodgkin’s lymphoma, diffuse large B-cell lymphoma, and non-small-cell lung cancer (NSCLC) ( Golding et al, 2018 ; Indini et al, 2020 ). Specially, rearrangements in the ALK are responsible for ∼3–5% of advanced NSCLC oncogenic driver mutations.…”

Section: Introductionmentioning

confidence: 99%

Deciphering the Mechanism of Gilteritinib Overcoming Lorlatinib Resistance to the Double Mutant I1171N/F1174I in Anaplastic Lymphoma Kinase

Liang

Wang

et al. 2021

Front. Cell Dev. Biol.

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Anaplastic lymphoma kinase (ALK) is validated as a therapeutic molecular target in multiple malignancies, such as non-small cell lung cancer (NSCLC). However, the feasibility of targeted therapies exerted by ALK inhibitors is inevitably hindered owing to drug resistance. The emergence of clinically acquired drug mutations has become a major challenge to targeted therapies and personalized medicines. Thus, elucidating the mechanism of resistance to ALK inhibitors is helpful for providing new therapeutic strategies for the design of next-generation drug. Here, we used molecular docking and multiple molecular dynamics simulations combined with correlated and energetical analyses to explore the mechanism of how gilteritinib overcomes lorlatinib resistance to the double mutant ALK I1171N/F1174I. We found that the conformational dynamics of the ALK kinase domain was reduced by the double mutations I1171N/F1174I. Moreover, energetical and structural analyses implied that the double mutations largely disturbed the conserved hydrogen bonding interactions from the hinge residues Glu1197 and Met1199 in the lorlatinib-bound state, whereas they had no discernible adverse impact on the binding affinity and stability of gilteritinib-bound state. These discrepancies created the capacity of the double mutant ALK I1171N/F1174I to confer drug resistance to lorlatinib. Our result anticipates to provide a mechanistic insight into the mechanism of drug resistance induced by ALK I1171N/F1174I that are resistant to lorlatinib treatment in NSCLC.

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Pharmacotherapeutic advances with anaplastic lymphoma kinase inhibitors for the treatment of non-small cell lung cancer

Cited by 7 publications

References 56 publications

Potential Unreliability of Uncommon ALK, ROS1, and RET Genomic Breakpoints in Predicting the Efficacy of Targeted Therapy in NSCLC

Potential Unreliability of Uncommon ALK, ROS1, and RET Genomic Breakpoints in Predicting the Efficacy of Targeted Therapy in NSCLC

NovelTPR::ROS1Fusion Gene Activates MAPK, PI3K and JAK/STAT Signaling in an Infant-type Pediatric Glioma

Deciphering the Mechanism of Gilteritinib Overcoming Lorlatinib Resistance to the Double Mutant I1171N/F1174I in Anaplastic Lymphoma Kinase

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