Circulating tumor DNA reveals mechanisms of lorlatinib resistance in patients with relapsed/refractory ALK-driven neuroblastoma

Berko, Esther R.; Witek, Gabriela M.; Matkar, Smita; Petrova, Zaritza O.; Wu, Megan A.; Smith, Courtney M.; Daniels, Alex; Kalna, Joshua; Kennedy, Annie; Gostuski, Ivan; Casey, Colleen; Krytska, Kateryna; Gerelus, Mark; Pavlick, Dean C.; Ghazarian, Susan; Park, Julie R.; Marachelian, Araz; Maris, John M.; Goldsmith, Kelly; Radhakrishnan, Ravi; Lemmon, Mark A.; Mossé, Yaël P.

doi:10.1038/s41467-023-38195-0

Cited by 17 publications

(20 citation statements)

References 71 publications

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“…Although lorlatinib treatment has reportedly been more successful at delaying ALK inhibitor resistance compared with other ALK-TKIs, certain cancer models including relapsed ALK-F1174L neuroblastomas have been shown to eventually acquire resistance after long-term treatment ( 22–24, 45, 46 ). To examine whether TNO155 could restore sensitivity in resistant ALK-F1174L neuroblastomas, we first generated a lorlatinib-resistant cell line model based on previously reported methodologies ( 24, 47, 48 ).…”

Section: Resultsmentioning

confidence: 99%

SHP2 Inhibition with TNO155 Increases Efficacy and Overcomes Resistance of ALK Inhibitors in Neuroblastoma

Valencia-Sama,

Kee,

Christopher

et al. 2023

Cancer Research Communications

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Survival rates among patients with high-risk neuroblastoma remain low and novel therapies for recurrent neuroblastomas are required. ALK is commonly mutated in primary and relapsed neuroblastoma tumors and ALK tyrosine kinase inhibitors (TKI) are promising treatments for ALK-driven neuroblastoma; however, innate or adaptive resistance to single-agent ALK-TKIs remain a clinical challenge. Recently, SHP2 inhibitors have been shown to overcome ALK-TKI resistance in lung tumors harboring ALK rearrangements. Here, we have assessed the efficacy of the SHP2 inhibitor TNO155 alone and in combination with the ALK-TKIs crizotinib, ceritinib, or lorlatinib for the treatment of ALK-driven neuroblastoma using in vitro and in vivo models. In comparison to wild-type, ALK-mutant neuroblastoma cell lines were more sensitive to SHP2 inhibition with TNO155. Moreover, treatment with TNO155 and ALK-TKIs synergistically reduced cell growth and promoted inactivation of ALK and MAPK signaling in ALK-mutant neuroblastoma cells. ALK-mutant cells engrafted into larval zebrafish and treated with single agents or dual SHP2/ALK inhibitors showed reduced growth and invasion. In murine ALK-mutant xenografts, tumor growth was likewise reduced or delayed, and survival was prolonged upon combinatorial treatment of TNO155 and lorlatinib. Finally, we show that lorlatinib-resistant ALK-F1174L neuroblastoma cells harbor additional RAS-MAPK pathway alterations and can be resensitized to lorlatinib when combined with TNO155 in vitro and in vivo. Our results report the first evaluation of TNO155 in neuroblastoma and suggest that combinatorial inhibition of ALK and SHP2 could be a novel approach to treating ALK-driven neuroblastoma, potentially including the increasingly common tumors that have developed resistance to ALK-TKIs. Significance: These findings highlight the translatability between zebrafish and murine models, provide evidence of aberrant RAS-MAPK signaling as an adaptive mechanism of resistance to lorlatinib, and demonstrate the clinical potential for SHP2/ALK inhibitor combinations for the treatment of ALK-mutant neuroblastoma, including those with acquired tolerance or potentially resistance to ALK-TKIs.

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Section: Resultsmentioning

confidence: 99%

SHP2 Inhibition with TNO155 Increases Efficacy and Overcomes Resistance of ALK Inhibitors in Neuroblastoma

Valencia-Sama,

Kee,

Christopher

et al. 2023

Cancer Research Communications

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“…Clinical trials for ALK TKIs in the treatment of paediatric malignancies including NB are in their relative infancy 22 , 42 – 46 . Nevertheless, de novo and acquired resistance can occur for all first, second, and third generation ALK inhibitors, thereby making ALK TKI efficacy challenging 2 , 3 , 41 , 47 – 49 . Hence, additional targets for combination treatments of NB and ALK-aberrant cancers are urgently needed 1 – 3 , 8 , 9 .…”

Section: Discussionmentioning

confidence: 99%

Targeting NRAS via miR-1304-5p or farnesyltransferase inhibition confers sensitivity to ALK inhibitors in ALK-mutant neuroblastoma

Pucci,

Lee,

Han

et al. 2024

Nat Commun

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Targeting Anaplastic lymphoma kinase (ALK) is a promising therapeutic strategy for aberrant ALK-expressing malignancies including neuroblastoma, but resistance to ALK tyrosine kinase inhibitors (ALK TKI) is a distinct possibility necessitating drug combination therapeutic approaches. Using high-throughput, genome-wide CRISPR-Cas9 knockout screens, we identify miR-1304-5p loss as a desensitizer to ALK TKIs in aberrant ALK-expressing neuroblastoma; inhibition of miR-1304-5p decreases, while mimics of this miRNA increase the sensitivity of neuroblastoma cells to ALK TKIs. We show that miR-1304-5p targets NRAS, decreasing cell viability via induction of apoptosis. It follows that the farnesyltransferase inhibitor (FTI) lonafarnib in addition to ALK TKIs act synergistically in neuroblastoma, inducing apoptosis in vitro. In particular, on combined treatment of neuroblastoma patient derived xenografts with an FTI and an ALK TKI complete regression of tumour growth is observed although tumours rapidly regrow on cessation of therapy. Overall, our data suggests that combined use of ALK TKIs and FTIs, constitutes a therapeutic approach to treat high risk neuroblastoma although prolonged therapy is likely required to prevent relapse.

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“…Furthermore, for numerous drug-resistant ALK mutations, enhanced ATP-binding affinity has also been reported ( Li et al, 2018 ). Similarly, the existence of a closed (occluded) drug binding site or a decrease in lorlatinib binding energy were both considered as potential causes of resistance in the computational kinetic model of lorlatinib competitive binding to ALK TKD in the presence of ALK ( Berko et al, 2023 ). Lorlatinib exhibits notable clinical benefits, particularly in advanced ALK-positive NSCLC with intensive previous treatment ( Baldacci et al, 1990 ).…”

Section: Discussionmentioning

confidence: 99%

A computational examination of the therapeutic advantages of fourth-generation ALK inhibitors TPX-0131 and repotrectinib over third-generation lorlatinib for NSCLC with ALK F1174C/L/V mutations

Balasundaram,

Doss

2024

Front. Mol. Biosci.

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Background: In non-small-cell lung cancer (NSCLC), a pivotal factor in promoting cancer development is the rearrangement in the anaplastic lymphoma kinase ALK gene, resulting in elevated ALK protein expression. F1174C/L/V is the acquired secondary resistant mutation in ALK. Significant survival improvements have been seen while tyrosine kinase inhibitors specifically target ALK. Nevertheless, the emergence of drug resistance hinders the clinical effectiveness of these drugs.Objective: This research sought to find the binding affinity/inhibitory effects of the existing drug lorlatinib (LOR) and upcoming TPX-0131 (zotizalkib/TPX) and repotrectinib (TPX-0005/REP) inhibitors against ALK F1174C/L/V mutations using computational approaches to identify potential strategies over resistance.Methods: We conducted molecular docking, molecular dynamics simulation, and MMPBSA calculations to investigate how compact macrocyclic inhibitors, such as TPX-0131 and repotrectinib, fit within the ATP-binding boundary and differ from LOR.Results: Our results demonstrated that TPX-0131 and repotrectinib contributed to higher binding energy in F1174C and F1174L mutations than LOR. Repotrectinib showed greater binding energy in the F1174V mutation, whereas LOR and TPX-0131 exhibited similar binding energy. However, all three inhibitors showed significant binding energy toward F1174C/L/V mutations found in NSCLC.Conclusion: This comparative study of the potential binding effects of fourth-generation inhibitors TPX-0131 and repotrectinib and third-generation inhibitor LOR for ALK F1174C/L/V mutations revealed the atomistic insights of the binding mechanism. These computational findings enable us to carry out further research for the clinical implementation of fourth-generation ALK inhibitors on ALK-positive NSCLC.

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Circulating tumor DNA reveals mechanisms of lorlatinib resistance in patients with relapsed/refractory ALK-driven neuroblastoma

Cited by 17 publications

References 71 publications

SHP2 Inhibition with TNO155 Increases Efficacy and Overcomes Resistance of ALK Inhibitors in Neuroblastoma

SHP2 Inhibition with TNO155 Increases Efficacy and Overcomes Resistance of ALK Inhibitors in Neuroblastoma

Targeting NRAS via miR-1304-5p or farnesyltransferase inhibition confers sensitivity to ALK inhibitors in ALK-mutant neuroblastoma

A computational examination of the therapeutic advantages of fourth-generation ALK inhibitors TPX-0131 and repotrectinib over third-generation lorlatinib for NSCLC with ALK F1174C/L/V mutations

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