4. You develop the covalently-acting irreversible kinase inhibitor ibrutinib shown on the left that reacts potently with a cysteine in the ATP binding pocket of the cancer-promoting kinase Bruton's Tyrosin Kinase (BTK). You would like to know whether ibrutinib engages and selectively targets BTK in vivo in the tumor of a mouse model of cancer. Describe experimentally how you would use activity-based protein profiling to assess whether ibrutinib inhibited BTK in vivo in the tumor and also determine how selectively ibrutinib engaged BTK compared to other kinases in the tumor? ( NH, H₂N- N ibrutinib OH OH OH OH activity-based probe for kinases that covalently modifies active-site lysine of all kinase ATP binding pocket W ta t C

You have developed an activator of a non-receptor tyrosine kinase. In three different cell types that all contain this receptor your drug has different effects. In cell type A you see activation of gene X and gene Y; in cell type B you note activation of Gene X, but no change in the mRNA levels for Gene Y. In cell type C your drug has no effect on either Gene X or Y. Describe how could each choice (A-D) be a possibility to suit the scenario? a. Genes X & Y are controlled by two separate STATs (STAT X & STAT Y). Cell type A contains both STATs; cell type B contains STAT X only; cell type C has neither STAT. b. Genes X & Y are controlled by two separate STATs (STAT X & STAT Y) and two separate JAKs (JAK X & JAK Y). Cell type A contains both STATs and JAKs; cell type B contains both STATs but JAK X only; cell type C has both STATs but neither JAK. c. Genes X & Y are controlled by two separate STATs (STAT X & STAT Y), two separate JAKs (JAK X & JAK Y) and…

Mutation in the fibroblast growth factor receptor (FGFR) gene results in achondroplasia (dwarfism), which is a dominant condition caused by a single base substitution (GGG>AGG) that changes the amino acid glycine at position 480 to arginine (G480R) in the FGFR protein. FGFR is normally active when FGF binds to it, but the mutant FGFR is always on to stimulate signaling that inhibits excessive bone growth. How can gene therapy be used to treat achondroplasia? Select all that apply. RNAi that knocks down the mutant FGFR expression Adeno-associated viral (AAV) vector that carries the wild-type FGFR Retroviral vector that carries the wild-type FGFR CRISPR with the wild-type FGFR donor DNA

The mechanisms that “trigger” micrometastases to develop into macrometastases (which can be clinically detected) are still poorly understood. However, elucidating these pathways could offer valuable insights into the long term treatment of cancer patients. Interestingly, the efficiency of this process is believed to be very low (indeed, many patients exhibit micrometastases that never develop into full blown clinical metastases). Which mechanism has a stronger influence on the outcome of colonization? What is the main driver leading to the development of macrometastases from micrometastases?