Notch3-dependent β-catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC

EGFR tyrosine kinase inhibitors cause dramatic responses in EGFR-mutant lung cancer, but resistance universally develops. The involvement of β-catenin in EGFR TKI resistance has been previously reported, however, the precise mechanism by which β-catenin activation contributes to EGFR TKI resistance is not clear. Here, we show that EGFR inhibition results in the activation of β-catenin signaling in a Notch3-dependent manner, which facilitates the survival of a subset of cells that we call “adaptive persisters”. We previously reported that EGFR-TKI treatment rapidly activates Notch3, and here we describe the physical association of Notch3 with β-catenin, leading to increased stability and activation of β-catenin. We demonstrate that the combination of EGFR-TKI and a β-catenin inhibitor inhibits the development of these adaptive persisters, decreases tumor burden, improves recurrence free survival, and overall survival in xenograft models. These results supports combined EGFR-TKI and β-catenin inhibition in patients with EGFR mutant lung cancer

Does Higher Gadolinium Concentration Play a Role in the Morphologic Assessment of Brain Tumors? Results of a Multicenter Intraindividual Crossover Comparison of Gadobutrol versus Gadobenate Dimeglumine (the MERIT Study)

BACKGROUND AND PURPOSE:Gadobenate dimeglumine has proved advantageous compared with other gadolinium-based contrast agents for contrast-enhanced brain MR imaging. Gadobutrol is a more highly concentrated agent (1.0 mol/L). This study intraindividually compared 0.1-mmol/kg doses of these agents for qualitative and quantitative evaluation of brain tumors.MATERIALS AND METHODS:Adult patients with suspected or known brain tumors underwent 2 identical MR imaging examinations at 1.5T, 1 with gadobenate dimeglumine and the other with gadobutrol, both at a dose of 0.1-mmol/kg body weight. The agents were injected in randomized order separated by 3-14 days. Imaging sequences and acquisition timing were identical for the 2 examinations. Three blinded readers evaluated images qualitatively for diagnostic information (lesion extent, delineation, morphology, enhancement, global preference) and quantitatively for CNR and LBR.RESULTS:One hundred fourteen of 123 enrolled patients successfully underwent both examinations. Final diagnoses were intra-axial tumors, metastases, extra-axial tumors, "other" tumors, and "nontumor" (49, 46, 8, 7, and 4 subjects, respectively). Readers 1, 2, and 3 demonstrated preference for gadobenate dimeglumine in 46 (40.7\%), 54 (47.4\%), and 49 (43.0\%) patients, respectively, compared with 6, 7, and 7 patients for gadobutrol (P < .0001, all readers). Highly significant (P < .0001, all readers) preference for gadobenate dimeglumine was demonstrated for all other qualitative end points. Inter-reader agreement was good for all evaluations (κ = 0.414-0.629). Significantly superior CNR and LBR were determined for gadobenate dimeglumine (P < .019, all readers).CONCLUSIONS:Significantly greater morphologic information and lesion enhancement are achieved on brain MR imaging with 0.1-mmol/kg gadobenate dimeglumine compared with gadobutrol at an equivalent dose

Early death during chemotherapy in patients with small-cell lung cancer: derivation of a prognostic index for toxic death and progression

Based on an increased frequency of early death (death within the first treatment cycle) in our two latest randomized trials of combination chemotherapy in small-cell lung cancer (SCLC), we wanted to identify patients at risk of early non-toxic death (ENTD) and early toxic death (ETD). Data were stored in a database and logistic regression analyses were performed to identify predictive factors for early death. During the first cycle, 118 out of 937 patients (12.6%) died. In 38 patients (4%), the cause of death was sepsis. Significant risk factors were age, performance status (PS), lactate dehydrogenase (LDH) and treatment with epipodophyllotoxins and platinum in the first cycle (EP). Risk factors for ENTD were age, PS and LDH. Extensive stage had a hazard ratio of 1.9 (P = 0.07). Risk factors for ETD were EP, PS and LDH, whereas age and stage were not. For EP, the hazard ratio was as high as 6.7 (P = 0.0001). We introduced a simple prognostic algorithm including performance status, LDH and age. Using a prognostic algorithm to exclude poor-risk patients from trials, we could minimize early death, improve long-term survival and increase the survival differences between different regimens. We suggest that other groups evaluate our algorithm and exclude poor prognosis patients from trials of dose intensification. © 1999 Cancer Research Campaig