The R1275Q Neuroblastoma Mutant and Certain ATP-competitive Inhibitors Stabilize Alternative Activation Loop Conformations of Anaplastic Lymphoma Kinase

Epstein, Linda F.; Chen, Hao; Emkey, Renee; Whittington, Douglas A.

doi:10.1074/jbc.m112.391425

Cited by 38 publications

(49 citation statements)

References 63 publications

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“…A similar dichotomous pattern of response has been observed with the two most common ALK mutations found in neuroblastoma, Alk-F1174L and Alk-R1275Q. Each of these mutants accounts for ∼40% of all ALK mutations in this disease, and shows a selective response to either type II inhibitors like crizotinib, as in the case of Alk-F1174L, or type I inhibitors like TAE684, as is the case for Alk-R1275Q ( Bresler et al , 2011 ; Epstein et al , 2012 ).…”

Section: Drugs That Do Not Kill Vs Cells That Woulsupporting

confidence: 59%

Targeting molecular addictions in cancer

Vivanco

2014

Br J Cancer

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Cancer cells depend on a finite number of critical signals for their survival. Oncogene addiction, that is, the acquired dependence of a cancer cell on the activity of a single oncogenic gene product, has been the basis for the targeted therapy paradigm, and operationally defines such signals. Additionally, cancer cells have altered metabolic requirements that create addictions to specific nutrients such as glucose and glutamine. In this review, I will discuss the therapeutic opportunities that these two types of molecular addictions offer, focusing on lessons learned from targeting members of the epidermal growth factor receptor family of kinases, and components of MAPK pathway. I will also discuss the challenges in simultaneously harnessing two types of molecular addictions for therapeutic benefit, and the importance of understanding not only the effects of oncogenic signal transduction on metabolism, but also the impact of metabolic states on signal transduction.

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Section: Drugs That Do Not Kill Vs Cells That Woulsupporting

confidence: 59%

Targeting molecular addictions in cancer

Vivanco

2014

Br J Cancer

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“…One possibility is to develop and optimize type II inhibitors for ALK. Although a preclinical type II ALK scaffold has been described (63), to our knowledge, there are no reported clinical TKIs that engage the inactive conformation of ALK. Whether such TKIs would demonstrate differential efficacy over their type I binding counterparts remains to be seen although the possibility of a nonoverlapping resistance profile might offer additional options for patients with refractory ALK-rearranged disease.…”

Section: Discussionmentioning

confidence: 99%

Structural insight into selectivity and resistance profiles of ROS1 tyrosine kinase inhibitors

Davare

Vellore

Wagner

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Oncogenic ROS1 fusion proteins are molecular drivers in multiple malignancies, including a subset of non-small cell lung cancer (NSCLC). The phylogenetic proximity of the ROS1 and anaplastic lymphoma kinase (ALK) catalytic domains led to the clinical repurposing of the Food and Drug Administration (FDA)-approved ALK inhibitor crizotinib as a ROS1 inhibitor. Despite the antitumor activity of crizotinib observed in both ROS1-and ALK-rearranged NSCLC patients, resistance due to acquisition of ROS1 or ALK kinase domain mutations has been observed clinically, spurring the development of second-generation inhibitors. Here, we profile the sensitivity and selectivity of seven ROS1 and/or ALK inhibitors at various levels of clinical development. In contrast to crizotinib's dual ROS1/ALK activity, cabozantinib (XL-184) and its structural analog foretinib (XL-880) demonstrate a striking selectivity for ROS1 over ALK. Molecular dynamics simulation studies reveal structural features that distinguish the ROS1 and ALK kinase domains and contribute to differences in binding site and kinase selectivity of the inhibitors tested. Cell-based resistance profiling studies demonstrate that the ROS1-selective inhibitors retain efficacy against the recently reported CD74-ROS1 G2032R mutant whereas the dual ROS1/ALK inhibitors are ineffective. Taken together, inhibitor profiling and stringent characterization of the structure-function differences between the ROS1 and ALK kinase domains will facilitate future rational drug design for ROS1-and ALK-driven NSCLC and other malignancies.onstitutively activated kinase fusion proteins that arise from somatic chromosomal rearrangements are frequent drivers of malignant transformation in cancer and represent a targetable vulnerability for clinical intervention. The clinical success of the tyrosine kinase inhibitor (TKI) imatinib in targeting the oncogenic BCR-ABL1 fusion protein in chronic myeloid leukemia (CML) motivated efforts to identify and target oncogenic kinases in other cancers (1-3). One such setting is non-small cell lung cancer (NSCLC), where chromosomal rearrangements of the receptor tyrosine kinase (RTK) anaplastic lymphoma kinase (ALK) are found in 4-5% of patients (4, 5). The validation of rearranged ALK as an oncogenic driver prompted the discovery and clinical implementation of crizotinib as the first clinical targeted inhibitor for use in ALK fusionpositive NSCLC (6, 7).Fusion proteins involving the highly related kinase ROS1, an orphan RTK of the insulin receptor family, are present in ∼1% of NSCLC patients. ROS1 rearrangements span a variety of fusion partners across several other epithelial malignancies, including cholangiocarcinoma, gastric cancer, and ovarian cancer (4, 8). CD74-ROS1 is the most frequent ROS1 fusion detected in NSCLC. ROS1 fusion proteins are transforming drivers that contribute to tumorigenesis or tumor progression in multiple experimental model systems (9)(10)(11).Approximately 75,000 and 15,000 new NSCLC patients per year are anticipated to harbor tumors...

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“…Using the Prime module of Schrödinger’s package, a knowledge-based model was built for both native ROS1 and ROS1 D2033N . The crystal structure of ALK (PDB entry 4FNY) (12) in the inactive state was used as a structural template (sequence homology ~64%) to build inactive ROS1. All four systems (ROS1 and ROS1 D2033N in both the active and inactive states) were solvated using a pre-equilibrated TIP3P water-box (13), maintaining a distance of 20 Å from any protein atom to the edge of the box.…”

Section: Methodsmentioning

confidence: 99%

A Novel Crizotinib-Resistant Solvent-Front Mutation Responsive to Cabozantinib Therapy in a Patient with ROS1-Rearranged Lung Cancer

Drilon

Somwar

Wagner

et al. 2016

Clinical Cancer Research

151

117

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Purpose Rearranged ROS1 is a crizotinib-sensitive oncogenic driver in lung cancer. The development of acquired resistance, however, poses a serious clinical challenge. Consequently, experimental and clinical validation of resistance mechanisms and potential second-line therapies is essential. Experimental Design We report the discovery of a novel, solvent-front ROS1D2033N mutation in a patient with CD74-ROS1-rearranged lung adenocarcinoma and acquired resistance to crizotinib. Crizotinib-resistance of CD74-ROS1D2033N was functionally evaluated using cell based assays and structural modelling. Results In biochemical and cell-based assays, the CD74-ROS1D2033N mutant demonstrated significantly decreased sensitivity to crizotinib. Molecular dynamics simulation revealed compromised crizotinib binding due to drastic changes in the electrostatic interaction between the D2033 residue and crizotinib and reorientation of neighboring residues. In contrast, cabozantinib binding was unaffected by the D2033N substitution and inhibitory potency against the mutant was retained. Notably, cabozantinib treatment resulted in a rapid clinical and near complete radiographic response in this patient. Conclusions These results provide the first example of successful therapeutic intervention with targeted therapy to overcome crizotinib resistance in a ROS1-rearranged cancer.

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The R1275Q Neuroblastoma Mutant and Certain ATP-competitive Inhibitors Stabilize Alternative Activation Loop Conformations of Anaplastic Lymphoma Kinase

Cited by 38 publications

References 63 publications

Targeting molecular addictions in cancer

Targeting molecular addictions in cancer

Structural insight into selectivity and resistance profiles of ROS1 tyrosine kinase inhibitors

A Novel Crizotinib-Resistant Solvent-Front Mutation Responsive to Cabozantinib Therapy in a Patient with ROS1-Rearranged Lung Cancer

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