A novel acquired ALK F1245C mutation confers resistance to crizotinib in ALK-positive NSCLC but is sensitive to ceritinib

Kodityal, Sandeep; Elvin, Julia A.; Squillace, Rachel M.; Agarwal, Nikita; Miller, Vincent A.; Ali, Siraj M.; Klempner, Samuel J.; Ou, Sai‐Hong Ignatius

doi:10.1016/j.lungcan.2015.11.023

Cited by 30 publications

(15 citation statements)

References 9 publications

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“…Potential reasons for lack of clinical activity include differences in ALK signaling events in different tumor types (i.e., “early” vs “late” events during tumor progression), differing tumor types, and genetics of the tumor cell, which may affect the response to ALK tyrosine kinase inhibitors . In addition, point mutations permitted in this study, for example F1174L and F1245C (common ALK ‐activating mutations seen in neuroblastoma), have been shown to confer resistance to crizotinib in neuroblastoma and other cancers . MYCN overexpression has also been associated with resistance to ALK inhibitors .…”

Section: Discussionmentioning

confidence: 95%

Long‐term effects of crizotinib in ALK‐positive tumors (excluding NSCLC): A phase 1b open‐label study

et al. 2018

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Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), MET, and ROS1, is approved for treatment of patients with ALK‐positive or ROS1‐positive advanced non‐small‐cell lung cancer (NSCLC). However, ALK rearrangements are also implicated in other malignancies, including anaplastic large‐cell lymphoma and inflammatory myofibroblastic tumors (IMTs). In this ongoing, multicenter, single‐arm, open‐label phase 1b study (PROFILE 1013; NCT01121588), patients with ALK‐positive advanced malignancies other than NSCLC were to receive a starting dose of crizotinib 250 mg twice daily. Primary endpoints were safety and objective responses based on Response Evaluation Criteria in Solid Tumors version 1.1 or National Cancer Institute International Response Criteria. Forty‐four patients were enrolled (lymphoma, n = 18; IMT, n = 9; other tumors, n = 17). The objective response rate was 53% (95% confidence interval [CI], 28–77) for lymphoma, with 8 complete responses (CRs) and 1 partial response (PR); 67% (95% CI, 30–93) for IMTs, with 1 CR and 5 PRs; and 12% (95% CI, 2–36) for other tumors, with 2 PRs in patients affected by colon carcinoma and medullary thyroid cancer, respectively. The median duration of treatment was almost 3 years for patients with lymphoma and IMTs, with 2‐year progression‐free survival of 63% and 67%, respectively. The most common treatment‐related adverse events were diarrhea (45.5%) and vision disorders (45.5%), mostly grade 1. These findings indicate strong and durable activity of crizotinib in ALK‐positive lymphomas and IMTs. The safety profile was consistent with the known safety profile of crizotinib even with long‐term treatment.

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Section: Discussionmentioning

confidence: 95%

Long‐term effects of crizotinib in ALK‐positive tumors (excluding NSCLC): A phase 1b open‐label study

et al. 2018

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“…Molecular modeling studies suggest that MET F1200I alters the conformation of the kinase domain such that it interferes with both the binding of type II MET TKIs within the DFG-out binding pocket, and to a lesser extent, may promote type I MET TKI resistance through disruption of an autoinhibitory MET conformation (Supplemental Figure S2) (7). Moreover, the F1200 residue is conserved across multiple tyrosine kinases, including ALK, ROS1, NTRK, and ABL, in which mutations at the corresponding residue have been linked to TKI resistance (Supplemental Table 4) (21)(22)(23)(24)(25)(26)(27).…”

Section: Both Met Second-site Mutations and Ras Pathway Alterations Amentioning

confidence: 99%

Co-occurring alterations in the RAS-MAPK pathway limit response to MET inhibitor treatment inMETexon 14 skipping mutation positive lung cancer

Rotow

Gui

et al. 2018

Preprint

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Abstract:While patients with advanced-stage non-small cell lung cancers (NSCLCs) harboring MET exon 14 skipping mutations (METex14) often benefit from MET tyrosine kinase inhibitor (TKI) treatment, their long-term survival is limited by drug resistance. The molecular basis for this resistance remains incompletely understood. Through targeted sequencing analysis of cell-free circulating tumor DNA obtained from 289 patients with advanced-stage METex14 NSCLC, we find prominent co-occurring RAS pathway gene alterations (e.g. in KRAS/NRAS, NF1). Clinical resistance to MET TKI treatment was associated with the presence of these co-occurring alterations. In a new preclinical model expressing a METex14 mutation, KRAS overexpression promoted MET TKI resistance, which was overcome by co-treatment with crizotinib and the MEK inhibitor trametinib. Our study provides a genetic landscape of co-occurring alterations in advanced-stage METex14-mutated NSCLC and suggests a potential combination therapy strategy to enhance clinical outcomes. Statement of Significance:This report describes targeted sequencing of the largest reported cohort of advanced-stage NSCLC with a MET exon 14 skipping mutation. The data uncover certain RAS pathway genetic alterations as potential mediators of MEK TKI resistance, which could be overcome by MEK and MET co-inhibition in NSCLC.Introduction:

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“…Moreover, the current availability of NGS methods allows the detection of further rare mutations in ALK kinase domain conferring either crizotinib sensitivity (67) or resistance, while allowing the inhibition exerted by second-generation inhibitors (68).…”

Section: The Issue Of Acquired Resistance To Crizotinibmentioning

confidence: 99%

Tackling ALK in non-small cell lung cancer: the role of novel inhibitors

Facchinetti¹,

Tiseo²,

Maïo³

et al. 2016

Transl. Lung Cancer Res.

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Abstract:Crizotinib is an oral inhibitor of anaplastic lymphoma kinase (ALK) with remarkable clinical activity in patients suffering from ALK-rearranged non-small cell lung cancer (NSCLC), accounting to its superiority compared to chemotherapy. Unfortunately, virtually all ALK-rearranged tumors acquire resistance to crizotinib, frequently within one year since the treatment initiation. To date, therapeutic strategies to overcome crizotinib resistance have focused on the use of more potent and structurally different compounds. Second-generation ALK inhibitors such as ceritinib (LDK378), alectinib (CH5424802/ RO5424802) and brigatinib (AP26113) have shown relevant clinical activity, consequently fostering their rapid clinical development and their approval by health agencies. The third-generation inhibitor lorlatinib (PF-06463922), selectively active against ALK and ROS1, harbors impressive biological potency; its efficacy in reversing resistance to crizotinib and to other ALK inhibitors is being proven by early clinical trials. The NTRK1-3 and ROS1 inhibitor entrectinib (RXDX-101) has been reported to act against NSCLC harboring ALK fusion proteins too. Despite the quick development of these novel agents, several issues remain to be discussed in the treatment of patients suffering from ALK-rearranged NSCLC. This position paper will discuss the development, the current evidence and approvals, as long as the future perspectives of new ALK inhibitors beyond crizotinib. Clinical behaviors of ALK-rearranged NSCLC vary significantly among patients and differential molecular events responsible of crizotinib resistance account for the most important quote of this heterogeneity. The precious availability of a wide range of active anti-ALK compounds should be approached in a critical and careful perspective, in order to develop treatment strategies tailored on the disease evolution of every single patient.

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A novel acquired ALK F1245C mutation confers resistance to crizotinib in ALK-positive NSCLC but is sensitive to ceritinib

Cited by 30 publications

References 9 publications

Long‐term effects of crizotinib in ALK‐positive tumors (excluding NSCLC): A phase 1b open‐label study

Long‐term effects of crizotinib in ALK‐positive tumors (excluding NSCLC): A phase 1b open‐label study

Co-occurring alterations in the RAS-MAPK pathway limit response to MET inhibitor treatment inMETexon 14 skipping mutation positive lung cancer

Tackling ALK in non-small cell lung cancer: the role of novel inhibitors

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