Acquired ALK L1152R Mutation Confers Resistance to Ceritinib and Predicts Response to Alectinib

Tchekmedyian, Nishan; Ali, Siraj M.; Miller, Vincent A.; Haura, Eric B.

doi:10.1016/j.jtho.2016.03.018

Cited by 23 publications

(12 citation statements)

References 5 publications

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“…The proportion of patients that develop ALK mutations in the setting of acquired resistance increases after treatment with the second-generation tyrosine kinase inhibitors (TKIs), alectinib and ceritinib. The ALK mutations most commonly found after TKI exposure include: L1196M for crizotinib, G1202R and compound ALK mutations after ceritinib, and G1202R after alectinib 4,5. Beyond ALK-dependent mechanisms of acquired resistance, the activation of alternative pathway-mediated survival signals (bypass pathways involving epidermal growth factor receptor [EGFR], KIT, insulin growth factor 1 receptor [IGF-1R], hepatocyte growth factor receptor MET/HGFR, and Kirsten rat sarcoma) has been observed.…”

Section: Introductionmentioning

confidence: 99%

The activity, safety, and evolving role of brigatinib in patients with <em>ALK</em>-rearranged non-small cell lung cancers

Sabari

Santini

Schram

et al. 2017

OTT

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Brigatinib (AP26113) is a dimethylphosphine oxide group-containing tyrosine kinase inhibitor (TKI) constructed around a bisanilinopyrimidine scaffold with potent activity against the anaplastic lymphoma kinase (ALK) and several other targets. Despite the activity of first- and second-generation ALK inhibitors in advanced ALK-rearranged lung cancers, the development of acquired resistance represents an ongoing challenge. Later generation ALK inhibitors such as brigatinib are important potential tools in the management of patients with acquired resistance characterized by continued dependency on ALK. Brigatinib is active in vitro against many ALK kinase domain mutations that may mediate acquired resistance to other ALK TKIs, with reported activity (IC50 <50 nM) against ALK C1156Y, I1171S/T, V1180L, L1196M, L1152R/P, E1210K, and G1269A. In patients with ALK-rearranged lung cancers who receive brigatinib after crizotinib, substantial and durable responses and intracranial disease control can be achieved based on early-phase clinical trial data. The drug is also being explored in TKI-naïve patients. From a safety perspective, early pulmonary toxicity has been observed, prompting the decision to pursue lead-in dosing for the drug. Early data point to ALK G1202R and ALK E1210K as potential mechanisms of clinical resistance to brigatinib.

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Section: Introductionmentioning

confidence: 99%

The activity, safety, and evolving role of brigatinib in patients with <em>ALK</em>-rearranged non-small cell lung cancers

Sabari

Santini

Schram

et al. 2017

OTT

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“…Unlike other ALK inhibitors, the crystal structural analysis of alectinib exhibits only one hinge hydrogen bond with kinase, indicating that this compound may achieve higher selectivity for ALK [39]. In prior studies, alectinib has shown substantial inhibitory effects against tumors with ALK mutations, including ALK L1196M , ALK L1152R , ALK F1174L , and ALK R1275Q [28, 35, 40, 48, 55]. Furthermore, chemoresistant cells harboring crizotinib-mediated ALK mutations ALK F1174L [10, 47] are sensitive to alectinib.…”

Section: Introductionmentioning

confidence: 99%

The second-generation ALK inhibitor alectinib effectively induces apoptosis in human neuroblastoma cells and inhibits tumor growth in a TH-MYCN transgenic neuroblastoma mouse model

Guan

Zhao

et al. 2017

Cancer Letters

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Activating germline mutations of anaplastic lymphoma kinase (ALK) occur in most cases of hereditary neuroblastoma (NB) and the constitutively active kinase activity of ALK promotes cell proliferation and survival in NB. Therefore, ALK kinase is a potential therapeutic target for NB. In this study, we show that the novel ALK inhibitor alectinib effectively suppressed cell proliferation and induces apoptosis in NB cell lines with either wild-type ALK or mutated ALK (F1174L and D1091N) by blocking ALK-mediated PI3K/Akt/mTOR signaling. In addition, alectinib enhanced doxorubicin-induced cytotoxicity and apoptosis in NB cells. Furthermore, alectinib induced apoptosis in an orthotopic xenograft NB mouse model. Also, in the TH-MYCN transgenic mouse model, alectinib resulted in decreased tumor growth and prolonged survival time. These results indicate that alectinib may be a promising therapeutic agent for the treatment of NB.

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“…The frequency of these mutations increases with each line of therapy as the sensitivity to different ALKi varies. For ceritinib, I1123S, L1152R, F1174C/V and G1202R have been identified clinically as resistance mutations . For alectinib, I1171N/T/S and G1202R produce resistance; while brigatinib is ineffective in the presence of G1202R .…”

Section: Discussionmentioning

confidence: 99%

“…For ceritinib, I1123S, L1152R, F1174C/V and G1202R have been identified clinically as resistance mutations . For alectinib, I1171N/T/S and G1202R produce resistance; while brigatinib is ineffective in the presence of G1202R . For alectinib, I1171N/T/S and G1202R confer resistance; while brigatinib is G1202R sensitive .…”

Section: Discussionmentioning

confidence: 99%

Treatment of ALK‐rearranged non‐small cell lung cancer: A review of the landscape and approach to emerging patterns of treatment resistance in the Australian context

Itchins

Chia

Hayes

et al. 2017

Asia-Pac J Clncl Oncology

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Since the identification of anaplastic lymphoma kinase (ALK) gene rearrangements in non-small cell lung cancer (NSCLC) in 2005, the treatment of ALK-rearranged NSCLC (ALK+ NSCLC) has evolved at a rapid pace. This molecularly distinct subset of NSCLC has uniquely important biology, clinicopathologic features and mechanisms of drug resistance which impact on the choice of treatment for a patient with this disease. There are multiple ALK tyrosine kinase inhibitors now available in clinical practice with efficacy data continuing to emerge and guide the optimal treatment algorithm. A detailed search of medical databases and clinical trial registries was conducted to capture all relevant articles on this topic enabling an updated detailed overview of the landscape of management of ALK-rearranged NSCLC.

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Acquired ALK L1152R Mutation Confers Resistance to Ceritinib and Predicts Response to Alectinib

Cited by 23 publications

References 5 publications

The activity, safety, and evolving role of brigatinib in patients with <em>ALK</em>-rearranged non-small cell lung cancers

The activity, safety, and evolving role of brigatinib in patients with <em>ALK</em>-rearranged non-small cell lung cancers

The second-generation ALK inhibitor alectinib effectively induces apoptosis in human neuroblastoma cells and inhibits tumor growth in a TH-MYCN transgenic neuroblastoma mouse model

Treatment of ALK‐rearranged non‐small cell lung cancer: A review of the landscape and approach to emerging patterns of treatment resistance in the Australian context

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