// Rajani Kanteti 1 , Surinder K. Batra 2 , Frances E. Lennon 1 and Ravi Salgia 3 1 Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA 2 Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA 3 Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA, USA Correspondence to: Ravi Salgia, email: // Keywords : FAK, paxillin, pancreatic cancer, integrins, P53 Received : October 22, 2015 Accepted : February 11, 2016 Published : March 13, 2016 Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer in large part due to late diagnosis and a lack of effective screening tests. In spite of recent progress in imaging, surgery and new therapeutic options for pancreatic cancer, the overall five-year survival still remains unacceptably low. Numerous studies have shown that focal adhesion kinase (FAK) is activated in many cancers including PDAC and promotes cancer progression and metastasis. Paxillin, an intracellular adaptor protein that plays a key role in cytoskeletal organization, connects integrins to FAK and plays a key role in assembly and disassembly of focal adhesions. Here, we have reviewed evidence in support of FAK as a potential therapeutic target and summarized related combinatorial therapies.
<p>Supplementary Table 1. Tumor and sequencing information for Cohort 1, paired primary and metastatic gastric adenocarcinoma samples; Supplementary Table 2. 243-gene targeted panel used for sequencing of Cohort 2 samples; Supplementary Table 3: Wild type and mutant read counts for paired primary and metastatic samples in cohort 1; Supplementary Table 4. Clinical and pathologic characteristics of Cohort 2; Supplementary Table 5. Complete sequencing results of Cohort 2; Supplementary Table 6. Clinical characteristics of Cohort 3; Supplementary Table 7. Treatment assignment algorithm of PANGEA clinical trial; Supplementary Table 8. Clinical Characteristics and Response Data of evaluable patients in the PANGEA cohort (N = 21)</p>
There are a number of molecular abnormalities that can occur in normal cells to induce a malignant phenotype. Recently, the receptor tyrosine kinase anaplastic lymphoma kinase (ALK) has been shown to have gain-of-function when partnered with different proteins. As an example, on chromosome 2p, with inversion, there is translocation with generation of EML4-ALK tyrosine kinase in lung cancer. In a phase I trial, EML4-ALK patients were selected to determine the response to a potent small molecule tyrosine kinase inhibitor crizotinib (previously identified as PF02341066). Dramatic durable responses were observed with crizotinib at 250 mg twice a day (orally). Interestingly, crizotinib also has activity against MET receptor tyrosine kinase. We have previously shown that MET can be overexpressed, sometimes mutated, or sometimes amplified in lung cancer. Thus, this review will emphasize the characteristics of crizotinib, and detail the clinical experience.
MET is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and degraded by c-CBL E3-ubiquitin ligase. We investigated genetic variations of c-CBL in HNSCC and the relationship between c-CBL and MET expression. High MET, low c-CBL expression was detected in 10 cell lines and 73 tumor tissues. Two novel mutations (L254S, L281F), and the single nucleotide polymorphism (SNP) P782L were identified from archival tumor tissues. 27.3% of loss of heterozygosity was found at CBL locus. Ectopic expression of wild-type c-CBL in SCC-35 cells downregulated MET expression and decreased cell viability. These results suggest MET overexpression is related to altered c-CBL expression, which may influence tumorigenesis.
