ALK
                     G1269A mutation as a potential mechanism of acquired resistance to crizotinib in an ALK-rearranged inflammatory myofibroblastic tumor

Michels, Sebastian; Scheel, Andreas H.; Wündisch, Thomas; Heuckmann, Johannes M.; Menon, Roopika; Puesken, Michael; Kobe, Carsten; Pasternack, Helen; Heydt, Carina; Scheffler, Matthias; Fischer, Rieke; Schultheis, Anne M.; Merkelbach‐Bruse, Sabine; Heukamp, Lukas C.; Büttner, Reinhard; Wolf, Jürgen

doi:10.1038/s41698-017-0004-3

Cited by 31 publications

(19 citation statements)

References 10 publications

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“…ALK inhibitors have shown remarkable effects against ALK-driven tumors. Several studies have shown that crizotinib exhibits impressive therapeutic effects in patients with ALK-translocated IMT [11,21]. These results support the dependence of ALK-rearranged tumors on ALK-mediated signaling and suggest a therapeutic option for genetically identified patients with the aggressive form of this soft-tissue tumor.…”

Section: Discussionsupporting

confidence: 54%

ALK expressed in a gastrointestinal stromal tumor harboring PDGFRA p. D842V mutation:a case report

et al. 2020

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Background: Gastrointestinal stromal tumors (GISTs) are the most common type of adult mesenchymal neoplasms.The events that drive GIST oncogenesis are primarily KIT or PDGFRA mutations, which lead to the susceptibility of these tumors to small-molecule tyrosine kinase inhibitors such as imatinib and sunitinib. However, previous studies have shown that patients with a PDGFRA D842V mutation in GISTs have a very low rate of response to imatinib treatment. Therefore, novel tyrosine kinase inhibitors (TKIs) are currently being evaluated in clinical trials to treat GISTs harboring a PDGFRA D842V mutation. Anaplastic lymphoma kinase (ALK) overexpression was not expected to be present in the GIST, and it has been used as a biomarker to distinguish GISTs from other types of mesenchymal tumors. Case presentation: Here, we report a 37-year-old male patient who presented with a large mass in the right upper abdomen and was subsequently diagnosed with a GIST harboring a PDGFRA D842V mutation. We unexpectedly found that the GIST in this patient exhibited simultaneous ALK expression. Conclusions: This is the first case reported of a GIST with ALK expression. This rare phenomenon suggests that the diagnosis of a GIST cannot be excluded absolutely if a tumor exhibits ALK expression. In addition, ALK may be a potential therapeutic target for patients with imatinib-resistant stromal tumors.

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Section: Discussionsupporting

confidence: 54%

ALK expressed in a gastrointestinal stromal tumor harboring PDGFRA p. D842V mutation:a case report

et al. 2020

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“…The gene fusion event confers constitutive activation of ALK and treatment with crizotinib inhibited constitutive phosphorylation of ALK and activation of downstream PI3K and MAPK signaling cascades. 38 Recently, Michels et al 42 has demonstrated that an ALK p.G1269A mutation was detected in a patient with DCTN1-ALK fusion who developed acquired resistance to crizotinib. Unfortunately, we were unable to obtain a repeat biopsy in our patient and therefore we could not confirm if any new mutations in ALK could have possibly contributed to the emergence of therapeutic resistance.…”

Section: Discussionmentioning

confidence: 99%

A Phase I Trial of the MET/ALK/ROS1 Inhibitor Crizotinib Combined with the VEGF Inhibitor Pazopanib in Patients with Advanced Solid Malignancies

Piha-Paul¹,

Dumbrava²,

Nair³

et al. 2021

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Background Crizotinib inhibits ALK, MET and ROS1 tyrosine kinases but the development of resistance to monotherapy is an issue. The anti-angiogenic properties of pazopanib could overcome crizotinib drug resistance. Additionally, the anti-angiogenic properties of crizotinib could augment the clinical efficacy of pazopanib. Methods We evaluated the safety and responses in patients with advanced solid tumors treated with crizotinib and pazopanib. Results Eighty-two patients (median age 53 years, range 18–78 years) were enrolled. The median number of prior systemic therapies was 3 (range, 0–8). We were able to dose escalate to dose level 8 (crizotinib 250 mg twice daily and pazopanib 800 mg daily) with no MTD identified. Grade 3 or 4 toxicities were seen in 32% of patients with the highest prevalence being fatigue (n=9, 11%), diarrhea (n=6, 7%), vomiting (n=3, 4%), anemia (n=2, 2%) and ALT increased (n=2, 2%). Of the 82 patients, 61 (74%) had measurable disease by RECISTv1.1 and reached first restaging (6 weeks). Partial response (PR) was observed in 6/61 (10%) patients, and stable disease (SD) lasting ≥6 months was observed in 10/61 patients (16%) (total = 16/61 (26%) of patients with SD ≥6 months/PR). Conclusion Dose level 6 (crizotinib 200 mg twice daily and pazopanib 600 mg daily) was the most tolerable dosing of the combination and can be used in future studies. We also observed moderate clinical activity in patients with advanced solid tumors that had received numerous prior therapies.

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“…21 However, a report showed that ceritinib can overcome resistance to crizotinib caused by secondary mutations such as ALK G1296A. 22 After receiving ceritinib, patient 1 achieved PR. This case demonstrated L1196Q mutation can also be overcome by ceritinib.…”

Section: Discussionmentioning

confidence: 99%

<p>Efficacy and Resistance of ALK Inhibitors in Two Inflammatory Myofibroblastic Tumor Patients with ALK Fusions Assessed by Whole Exome and RNA Sequencing</p>

Zhang¹,

Wang²,

Zhuang³

et al. 2020

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We report two inflammatory myofibroblastic tumor (IMT) patients with ALK fusions (RRBP-ALK and TNS1-ALK, respectively). They both received tumor resection surgery and treatment with ALK inhibitors crizotinib followed by alectinib, and upon receiving each of the drugs, showed a brief response, then experienced recurrence or progression of the disease. During the treatment, whole exome sequencing (WES) and RNA sequencing (RNA-Seq) were applied to monitor potential drug-induced gene mutation and expression changes. A novel, secondary mutation in ALK exon 23 (L1196Q) was identified in patient 1 after alectinib resistance developed. Guided by this result, a newer ALK inhibitor, ceritinib was prescribed. The patient was able to achieve a partial response (PR) and is in good condition as of the manuscript date. On the contrary, there was no secondary mutation identified in ALK in patient 2 after drug resistance. While the expression of PTCH1, a negative regulator of the sonic hedgehog (SHH) signaling pathway, was significantly reduced at the time after the treatment with crizotinib before that of alectinib. The expression of PTCH1 was also reduced after the treatment with alectinib. It was reported that ALK can exert its biological functions partially by activating SHH signaling pathway. The down-regulation of PTCH1 suggests the compensatory activation of SHH pathway may cause resistance to ALK inhibitors in IMT. Going forward, monitoring gene mutation and expression changes through DNA and RNA sequencing will be able to offer opportunities to investigate potential mechanisms of drug resistance and will help to achieve precise prescription for better treatment outcomes.

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ALK G1269A mutation as a potential mechanism of acquired resistance to crizotinib in an ALK-rearranged inflammatory myofibroblastic tumor

Cited by 31 publications

References 10 publications

ALK expressed in a gastrointestinal stromal tumor harboring PDGFRA p. D842V mutation:a case report

ALK expressed in a gastrointestinal stromal tumor harboring PDGFRA p. D842V mutation:a case report

A Phase I Trial of the MET/ALK/ROS1 Inhibitor Crizotinib Combined with the VEGF Inhibitor Pazopanib in Patients with Advanced Solid Malignancies

<p>Efficacy and Resistance of ALK Inhibitors in Two Inflammatory Myofibroblastic Tumor Patients with ALK Fusions Assessed by Whole Exome and RNA Sequencing</p>

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