Mutations in the <i>DDR2</i> Kinase Gene Identify a Novel Therapeutic Target in Squamous Cell Lung Cancer

Hammerman, Peter S.; Sos, Martin L.; Ramos, Alex H.; Xu, Chunxiao; Dutt, Amit; Zhou, Wenjun; Brace, Lear E.; Woods, Brittany A.; Lin, Wenchu; Zhang, Jianming; Deng, Xianming; Lim, Sang Min; Heynck, Stefanie; Peifer, Martin; Simard, Jeffrey R.; Lawrence, Michael S.; Onofrio, Robert C.; Salvesen, Helga B.; Seidel, Danila; Zander, Thomas; Heuckmann, Johannes M.; Soltermann, Alex; Moch, Holger; Koker, Mirjam; Leenders, Frauke; Gabler, Franziska; Querings, Silvia; Ansén, Sascha; Brambilla, Élisabeth; Brambilla, Christian; Lorimier, Philippe; Brustugun, Odd Terje; Helland, Åslaug; Petersen, Iver; Clement, Joachim H.; Groen, Harry J.M.; Timens, Wim; Sietsma, Hannie; Stoelben, Erich; Wolf, Juergen; Beer, David G.; Tsao, Ming‐Sound; Hanna, Megan; Hatton, Charlie; Eck, Michael J.; Jänne, Pasi A.; Johnson, Bruce E.; Winckler, Wendy; Greulich, Heidi; Bass, Adam J.; Cho, Jeonghee; Rauh, Daniel; Gray, Nathanael S.; Wong, Kwok-Kin; Haura, Eric B.; Thomas, Roman K.; Meyerson, Matthew

doi:10.1158/2159-8274.cd-11-0005

Cited by 432 publications

(413 citation statements)

References 45 publications

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“…142 Discoidin domain receptor 2, a tyrosine kinase receptor that binds collagen as its endogenous ligand, has been previously shown to promote cell migration, proliferation, and survival when activated by ligand binding and phosphorylation. EGFRvIII mutations were found in 5% of human lung squamous cell carcinomas (also see prior discussion) (Figure 4).…”

Section: Other Alterations That Affect the Egfr Tki Responsementioning

confidence: 99%

Molecular pathology of lung cancer: key to personalized medicine

et al. 2012

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The majority of lung adenocarcinoma patients with epidermal growth factor receptor-(EGFR) mutated or EML4-ALK rearrangement-positive tumors are sensitive to tyrosine kinase inhibitors. Both primary and acquired resistance in a significant number of those patients to these therapies remains a major clinical problem. The specific molecular mechanisms associated with tyrosine kinase inhibitor resistance are not fully understood. Clinicopathological observations suggest that molecular alterations involving so-called 'driver mutations' could be used as markers that aid in the selection of patients most likely to benefit from targeted therapies. In this review, we summarize recent developments involving the specific molecular mechanisms and markers that have been associated with primary and acquired resistance to EGFR-targeted therapy in lung adenocarcinomas. Understanding these mechanisms may provide new treatment avenues and improve current treatment algorithms.

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Section: Other Alterations That Affect the Egfr Tki Responsementioning

confidence: 99%

Molecular pathology of lung cancer: key to personalized medicine

et al. 2012

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“…Only a few therapeutically tractable genome alterations have so far been found in squamous cell lung cancer ( 3,4 ) and smallcell lung cancer ( 5 ). Of these, amplifi cations of 8p12 ( FGFR1 , WHSC1L1 ) and mutations of DDR2 have been associated with preclinical sensitivity to kinase inhibition (6)(7)(8)(9). Furthermore, early signs of clinical activity of fi broblast growth factor receptor (FGFR) inhibitors in FGFR1 -amplifi ed small and squamous cell carcinomas underscore the validity of such approaches ( 10,11 ).…”

Section: Introductionmentioning

confidence: 99%

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of Transformation by Amplified FGFR1 in Lung Cancer

et al. 2014

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The 8p12 locus (containing the FGFR1 tyrosine kinase gene) is frequently amplifi ed in squamous cell lung cancer. However, it is currently unknown which of the 8p12-amplifi ed tumors are also sensitive to fi broblast growth factor receptor (FGFR) inhibition. We found that, in contrast with other recurrent amplifi cations, the 8p12 region included multiple centers of amplifi cation, suggesting marked genomic heterogeneity. FGFR1 -amplifi ed tumor cells were dependent on FGFR ligands in vitro and in vivo . Furthermore, ectopic expression of FGFR1 was oncogenic, which was enhanced by expression of MYC. We found that MYC was coexpressed in 40% of FGFR1 -amplifi ed tumors. Tumor cells coexpressing MYC were more sensitive to FGFR inhibition, suggesting that patients with FGFR1-amplifi ed and MYC-overexpressing tumors may benefi t from FGFR inhibitor therapy. Thus, both cell-autonomous and non-cell-autonomous mechanisms of transformation modulate FGFR dependency in FGFR1 -amplifi ed lung cancer, which may have implications for patient selection for treatment with FGFR inhibitors. SIGNIFICANCE:Amplifi cation of FGFR1 is one of the most frequent candidate targets in lung cancer. Here, we show that multiple factors affect the tumorigenic potential of FGFR1 , thus providing clinical hypotheses for refi nement of patient selection. Cancer Discov; 4(2);

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“…5 In non-small-cell lung cancer (NSCLC), recent investigations have uncovered other potentially actionable molecular alterations. 6,7 In solid tumors, these alterations are rare, and resistance develops within a relatively short time interval. 8 Chemotherapy produces response rates (RR) of 25% to 35% in treatment-naive NSCLC patients, suggesting that molecular markers can be used as determinants of treatment benefit.…”

Section: Introductionmentioning

confidence: 99%

Randomized International Phase III Trial of ERCC1 and RRM1 Expression–Based Chemotherapy Versus Gemcitabine/Carboplatin in Advanced Non–Small-Cell Lung Cancer

Bepler

Williams

Schell

et al. 2013

JCO

128

114

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A B S T R A C T PurposeWe assessed whether chemotherapy selection based on in situ ERCC1 and RRM1 protein levels would improve survival in patients with advanced non-small-cell lung cancer (NSCLC). Patients and MethodsEligible patients were randomly assigned 2:1 to the trial's experimental arm, which consisted of gemcitabine/carboplatin if RRM1 and ERCC1 were low, docetaxel/carboplatin if RRM1 was high and ERCC1 was low, gemcitabine/docetaxel if RRM1 was low and ERCC1 was high, and docetaxel/vinorelbine if both were high. In the control arm, patients received gemcitabine/ carboplatin. The trial was powered for a 32% improvement in 6-month progression-free survival (PFS). ResultsOf 331 patients registered, 275 were eligible. The median number of cycles given was four in both arms. A tumor rebiopsy specifically for expression analysis was required in 17% of patients. The median time from informed consent to expression analysis was 11 days. We found no statistically significant differences between the experimental arm and the control arm in PFS (6.1 months v 6.9 months) or overall survival (11.0 months v 11.3 months). A subset analysis revealed that patients with low levels for both proteins who received the same treatment in both treatment arms had a statistically better PFS (P ϭ .02) in the control arm (8.1 months) compared with the experimental arm (5.0 months). ConclusionThis demonstrates that protein expression analysis for therapeutic decision making is feasible in newly diagnosed patients with advanced-stage NSCLC. A tumor rebiopsy is safe, required in 17%, and acceptable to 89% (47 of 53) of patients.

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Mutations in the DDR2 Kinase Gene Identify a Novel Therapeutic Target in Squamous Cell Lung Cancer

Cited by 432 publications

References 45 publications

Molecular pathology of lung cancer: key to personalized medicine

Molecular pathology of lung cancer: key to personalized medicine

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of Transformation by Amplified FGFR1 in Lung Cancer

Randomized International Phase III Trial of ERCC1 and RRM1 Expression–Based Chemotherapy Versus Gemcitabine/Carboplatin in Advanced Non–Small-Cell Lung Cancer

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