Secondary Mutations at I1171 in the ALK Gene Confer Resistance to Both Crizotinib and Alectinib

Toyokawa, Gouji; Hirai, Fumihiko; Inamasu, Eiko; Yoshida, Tsukihisa; Nosaki, Kaname; Takenaka, Tomoyoshi; Yamaguchi, Masafumi; Seto, Takashi; Takenoyama, Mitsuhiro; Ichinose, Yukito

doi:10.1097/jto.0000000000000358

Cited by 70 publications

(64 citation statements)

References 8 publications

(7 reference statements)

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“…However, treatment with crizotinib is marked by heterogeneity in the magnitude and duration of patient response. Response durations vary from a few months to several years, and the long-term effectiveness of crizotinib is invariably limited by the development of acquired resistance (8)(9)(10)(11)(12)(13)(14)(15)(16). Mechanisms of acquired resistance have been identified in approximately 30% to 40% of crizotinib-resistant patients and have been distinguished into two main categories: those affecting the ALK-gene itself including additional genetic alterations through secondary mutations, gene amplification or gain of copy number, or those independent of the ALK-gene via other therapy-induced adaptive responses (15,17).…”

Section: Introductionmentioning

confidence: 99%

Circulating Tumor Cells with Aberrant ALK Copy Number Predict Progression-Free Survival during Crizotinib Treatment in ALK-Rearranged Non–Small Cell Lung Cancer Patients

et al. 2017

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The duration and magnitude of clinical response are unpredictable in ALK-rearranged non-small cell lung cancer (NSCLC) patients treated with crizotinib, although all patients invariably develop resistance. Here, we evaluated whether circulating tumor cells (CTC) with aberrant ALK-FISH patterns [ALK-rearrangement, ALK-copy number gain (ALK-CNG)] monitored on crizotinib could predict progression-free survival (PFS) in a cohort of ALK-rearranged patients. Thirty-nine ALK-rearranged NSCLC patients treated with crizotinib as first ALK inhibitor were recruited prospectively. Blood samples were collected at baseline and at an early time-point (2 months) on crizotinib. Aberrant ALK-FISH patterns were examined in CTCs using immunofluorescence staining combined with filter-adapted FISH after filtration enrichment. CTCs were classified into distinct subsets according to the presence of ALK-rearrangement and/or ALK-CNG signals. No significant association between baseline numbers of ALK-rearranged or ALK-CNG CTCs and PFS was observed. However, we observed a significant association between the decrease in CTC number with ALK-CNG on crizotinib and a longer PFS (likelihood ratio test, P ¼ 0.025). In multivariate analysis, the dynamic change of CTC with ALK-CNG was the strongest factor associated with PFS (HR, 4.485; 95% confidence interval, 1.543-13.030, P ¼ 0.006). Although not dominant, ALK-CNG has been reported to be one of the mechanisms of acquired resistance to crizotinib in tumor biopsies. Our results suggest that the dynamic change in the numbers of CTCs with ALK-CNG may be a predictive biomarker for crizotinib efficacy in ALK-rearranged NSCLC patients. Serial molecular analysis of CTC shows promise for realtime patient monitoring and clinical outcome prediction in this population. Cancer Res; 77(9); 2222-30. Ó2017 AACR.

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Section: Introductionmentioning

confidence: 99%

Circulating Tumor Cells with Aberrant ALK Copy Number Predict Progression-Free Survival during Crizotinib Treatment in ALK-Rearranged Non–Small Cell Lung Cancer Patients

et al. 2017

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“…Other mutations are identified as C1156Y, G1269A, F1174, L1152R, S1206Y, G1202R, and D1203N. 3,5,[12][13][14][15] The second generation ALK-inhibitors play a major role in those secondary mutations, which are the primary cause of resistance in cases progressed under crizotinib therapy (Table 2 …”

Section: Secondary Resistance Mutations In Alkmentioning

confidence: 99%

Treatment After Crizotinib Resistance in ALK+ Non-Small-Cell Lung Cancer

Kazaz¹

2017

UHOD

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Systemic chemotherapy, genotype-based targeted therapies and immunotherapy are widely used in the treatment of advanced nonsmall-cell lung cancer (NSCLC). Among the targeted therapies, the agents targeting the epidermal growth factor receptor (EGFR), the echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) rearrangement and C-ros oncogene 1 (ROS-1) have currently become standard treatment for cases presenting such molecular anomalies. Of them, cases with ALKrearrangement displayed dramatic results with a first generation ALK-inhibitor crizotinib; however, most of the patients develop a resistance in a few years. Especially the central nervous system relapses pose the most common clinical problem. Next generation ALK-inhibitors are promising with a high level of effectiveness in this resistance, in which various molecular mechanisms take part. Also, it gains increasing importance to re-perform a biopsy in the progression stage and reveal the mechanisms causing the secondary resistance in those patients. Keywords:Non-small-cell lung cancer, ALK, Crizotinib, Resistance ÖZET ALK-Pozitif Küçük Hücreli Dışı Akciğer Kanserinde Crizotinib Direnci Sonrası Tedaviİleri evre küçük hücreli dışı akciğer kanseri (KHDAK)'nin tedavisinde sistemik kemoterapi, genotipe dayalı hedef tedaviler ve immunoterapi yaygın olarak kullanılmaktadır. Hedef tedaviler arasında epidermal growth factor receptor (EGFR), the echinoderm microtubule-associated protein-like 4 anaplastic lypmhoma kinase (EML4-ALK) rearrangement ve C-ros oncogene 1 (ROS-1)'i hedefleyen ajanlar, bugün için bu moleküler anormalliklere sahip hastalarda standard tedavi haline gelmiştir. Bunlardan ALK-rearrangement'i olan hastalarda birinci jenerasyon ALK-inhibitörü crizotinib ile dramatik sonuçlar elde edilmiş olmakla birlikte hastaların çoğunda birkaç yıl içinde direnç gelişmektedir. Özellikle santral sinir sistemi relapsları en sık karşılaşılan klinik sorun olarak karşımıza çıkmaktadır. Çeşitli moleküler mekanizmaların rol oynadığı bu direnç durumunda yeni jenerasyon ALK-inhibitörleri yüksek etkinlikleri ile ümit vadetmektedir.Ayrıca bu hastalarda progresyon aşamasında tekrar biyopsi yapılması ve sekonder dirence neden olan mekanizmaların ortaya konması giderek önem kazanmaktadır.Anahtar Kelimeler: Küçük hücreli dışı akciğer kanseri, ALK, Crizotinib, Direnç

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“…3 groups reported that the mutations at I1171 (I1171T, I1171N, and I1171S) confer resistance to alectinib, and the structural analysis revealed that disruption of a hydrogen bond between alectinib and E1167 by the I1171T mutation contributed to the destabilization of the alectinib complex with the mutant kinase [32,34,35]. Importantly, the mutations at codon 1171 also mediate crizotinib resistance, which can be overcome by ceritinib [32,34]. Although V1180L also mediated a high resistance to alectinib in a cell line model, the mutation has yet to be identified in patients [34].…”

Section: Resistance Mechanisms To Alk Inhibitorsmentioning

confidence: 99%

“…With regard to the secondary ALK mutations which confer resistance to alectinib, 2 mutations at codons 1171 and 1202 were identified [32,33,34,35]. 3 groups reported that the mutations at I1171 (I1171T, I1171N, and I1171S) confer resistance to alectinib, and the structural analysis revealed that disruption of a hydrogen bond between alectinib and E1167 by the I1171T mutation contributed to the destabilization of the alectinib complex with the mutant kinase [32,34,35].…”

Section: Resistance Mechanisms To Alk Inhibitorsmentioning

confidence: 99%

Updated Evidence on the Mechanisms of Resistance to ALK Inhibitors and Strategies to Overcome Such Resistance: Clinical and Preclinical Data

Toyokawa

Seto

2015

Oncol Res Treat

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Anaplastic lymphoma kinase(ALK) rearrangement is one of the oncogenes in non-small cell lung cancer (NSCLC) identified in 2007. The PROFILE trials demonstrated that patients with ALK-rearranged NSCLC can be successfully treated with crizotinib, and that crizotinib is superior to chemotherapy in both first- and second-line settings. Furthermore, next-generation ALK inhibitors, such as alectinib and ceritinib, have been shown to harbor excellent efficacy for NSCLC patients with ALK rearrangement. However, it is known that many cases ultimately acquire resistance to ALK inhibitors. Some potential mechanisms of resistance to ALK inhibitors are as follows: ALK dominant resistance, such as secondary mutations and copy number gain in the ALK gene; activation of the bypass tracks, including EGFR, KRAS, KIT, MET, and IGF-1R. Furthermore, treatment strategies to overcome these resistance mechanisms have been proposed, and next-generation ALK inhibitors, agents which inhibit the bypass tracks, and heat shock protein 90 inhibitors are thought to be promising. Thus, clinical and pre-clinical evidence on the resistance mechanisms to ALK inhibitors and treatment strategies to overcome the resistance have been gradually obtained. Herein, we concisely review the current clinical and pre-clinical data regarding the mechanisms of resistance to ALK inhibitors and treatments to overcome such resistance.

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Secondary Mutations at I1171 in the ALK Gene Confer Resistance to Both Crizotinib and Alectinib

Cited by 70 publications

References 8 publications

Circulating Tumor Cells with Aberrant ALK Copy Number Predict Progression-Free Survival during Crizotinib Treatment in ALK-Rearranged Non–Small Cell Lung Cancer Patients

Circulating Tumor Cells with Aberrant ALK Copy Number Predict Progression-Free Survival during Crizotinib Treatment in ALK-Rearranged Non–Small Cell Lung Cancer Patients

Treatment After Crizotinib Resistance in ALK+ Non-Small-Cell Lung Cancer

Updated Evidence on the Mechanisms of Resistance to ALK Inhibitors and Strategies to Overcome Such Resistance: Clinical and Preclinical Data

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