c-Met receptor tyrosine kinase (RTK) has not been extensively studied in malignant pleural mesothelioma

Lung cancer is characterized by abnormal cell growth and invasion, and the actin cytoskeleton plays a major role in these processes. The focal adhesion protein paxillin is a target of a number of oncogenes involved in key signal transduction and important in cell motility and migration. In lung cancer tissues, we have found that paxillin was highly expressed (compared with normal lung), amplified (12.1%, 8 of 66) and correlated with increased MET and epidermal growth factor receptor (EGFR) gene copy numbers, or mutated (somatic mutation rate of 9.4%, 18 of 191). Paxillin mutations (19 of 21) were clustered between LD motifs 1 and 2 and the LIM domains. The most frequent point mutation (A127T) enhanced lung cancer cell growth, colony formation, focal adhesion formation, and colocalized with Bcl-2 in vitro. Gene silencing from RNA interference of mutant paxillin led to reduction of cell viability. A murine in vivo xenograft model of A127T paxillin showed an increase in tumor growth, cell proliferation, and invasion. These results establish an important role for paxillin in lung cancer. [Cancer Res 2008;68(1):132-42]

Purpose: c-Met is a receptor tyrosine kinase involved in cell growth, invasion, metastases, and angiogenesis. In this study, we investigated the role of c-Met in melanoma biology using a novel small-molecule tyrosine kinase inhibitor SU11274 and small interfering (si) RNA against the receptor. Experimental Design: The effects of SU11274 and c-Met siRNA were studied on proliferation, apoptosis, differentiation, reactive oxygen species, and intracellular signaling. c-Met mutations were examined, and the expression of c-Met and activated c-Met was studied in nevi, primary, and metastatic melanoma. Results: c-Met was expressed in 6:7 melanoma cell lines by immunoblotting. SU11274 inhibited cell growth in all melanoma cell lines by 85% to 98% with an IC 50 between 1and 2.5 Amol/L and caused apoptosis (12-58%) in five out of six cell lines. siRNA against c-Met inhibited proliferation of melanoma cells by 60%. This is the first study that shows that SU11274 and siRNA induced microphthalmia-associated transcription factor (MITF) and several other melanoma differentiation proteins and a morphologically differentiated phenotype. SU11274 also inhibited reactive oxygen species formation and phosphorylation of c-Met receptor, AKT and S-6 kinase by the hepatocyte growth factor. A new missense c-Met mutation N948S was identified in cell lines and R988C in tumor tissue in the juxtamembrane domain of c-Met. It was found that c-Met was expressed in 88% of melanomas and 15% of nevi, and that c-Met (pY1003) was activated in 21% of human melanomas. Conclusion: These results support the role of c-Met in proliferation, apoptosis, differentiation, and tumor progression of melanoma. SU11274 could be used in the therapeutic inhibition of melanoma.

BACKGROUND: Advancing health equity entails reducing disparities in care. African-American patients with chronic kidney disease (CKD) have poorer outcomes, including dialysis access placement and transplantation. Estimated glomerular filtration rate (eGFR) equations, which assign higher eGFR values to African-American patients, may be a mechanism for inequitable outcomes. Electronic health record-based registries enable population-based examination of care across racial groups. OBJECTIVE: To examine the impact of the race multiplier for African-Americans in the CKD-EPI eGFR equation on CKD classification and care delivery. DESIGN: Cross-sectional study SETTING: Two large academic medical centers and affiliated community primary care and specialty practices. PARTICIPANTS: A total of 56,845 patients in the Partners HealthCare System CKD registry in June 2019, among whom 2225 (3.9%) were African-American. MEASUREMENTS: Exposures included race, age, sex, comorbidities, and eGFR. Outcomes were transplant referral and dialysis access placement. RESULTS: Of 2225 African-American patients, 743 (33.4%) would hypothetically be reclassified to a more severe CKD stage if the race multiplier were removed from the CKD-EPI equation. Similarly, 167 of 687 (24.3%) would be reclassified from stage 3B to stage 4. Finally, 64 of 2069 patients (3.1%) would be reassigned from eGFR > 20 ml/min/1.73 m 2 to eGFR ≤ 20 ml/min/ 1.73 m 2 , meeting the criterion for accumulating kidney transplant priority. Zero of 64 African-American patients with an eGFR ≤ 20 ml/min/1.73 m 2 after the race multiplier was removed were referred, evaluated, or waitlisted for kidney transplant, compared to 19.2% of African-American patients with eGFR ≤ 20 ml/min/1.73 m 2 with the default CKD-EPI equation.LIMITATIONS: Single healthcare system in the Northeastern United States and relatively small African-American patient cohort may limit generalizability. CONCLUSIONS: Our study reveals a meaningful impact of race-adjusted eGFR on the care provided to the African-American CKD patient population.

The c-Met receptor tyrosine kinase is emerging as a novel target in many solid tumors, including lung cancer. PHA-665752 was identified as a small molecule, ATP competitive inhibitor of the catalytic activity of the c-Met kinase. Here, we show that treatment with PHA665752 reduced NCI-H69 (small cell lung cancer) and NCI-H441 (non-small cell lung cancer) tumorigenicity in mouse xenografts by 99% and 75%, respectively. Reduction in tumor size was also observed by magnetic resonance imaging of tumors in mice. PHA665752 inhibited c-Met phosphorylation at the autophosphorylation and c-Cbl binding sites in mouse xenografts derived from non-small cell lung cancer cell lines (NCI-H441 and A549) and small cell lung cancer cell line (NCI-H69). PHA665752 also inhibited angiogenesis by >85% in all the abovementioned cell lines and caused an angiogenic switch which resulted in a decreased production of vascular endothelial growth factor and an increase in the production of the angiogenesis inhibitor thrombospondin-1. These studies show the feasibility of selectively targeting c-Met with ATP competitive small molecule inhibitors and suggest that PHA665752 may provide a novel therapeutic approach to lung cancer. [Cancer Res 2007;67(8):3529-34]

Cancer is one of the most extreme medical conditions in both developing and developed countries around the world, causing millions of deaths each year. Chemotherapy and/or radiotherapy are key for treatment approaches, but both have numerous adverse health effects. Furthermore, the resistance of cancerous cells to anticancer medication leads to treatment failure. The rising burden of cancer overall requires novel efficacious treatment modalities. Natural medications offer feasible alternative options against malignancy in contrast to western medication. Furanocoumarins’ defensive and restorative impacts have been observed in leukemia, glioma, breast, lung, renal, liver, colon, cervical, ovarian, and prostate malignancies. Experimental findings have shown that furanocoumarins activate multiple signaling pathways, leading to apoptosis, autophagy, antioxidant, antimetastatic, and cell cycle arrest in malignant cells. Additionally, furanocoumarins have been shown to have chemo preventive and chemotherapeutic synergistic potential when used in combination with other anticancer drugs. Here, we address different pathways which are activated by furanocoumarins and their therapeutic efficacy in various tumors. Ideally, this review will trigger interest in furanocoumarins and their potential efficacy and safety as a cancer lessening agents.

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