Interaction of the T cell receptor (TCR) with an MHC-antigenic peptide complex results in changes at the molecular and cellular levels in T cells. The outside environmental cues are translated into various signal transduction pathways within the cell, which mediate the activation of various genes with the help of specific transcription factors. These signaling networks propagate with the help of various effector enzymes, such as kinases, phosphatases, and phospholipases. Integration of these disparate signal transduction pathways is done with the help of adaptor proteins that are non-enzymatic in function and that serve as a scaffold for various protein–protein interactions. This process aids in connecting the proximal to distal signaling pathways, thereby contributing to the full activation of T cells. This review provides a comprehensive snapshot of the various molecules involved in regulating T cell receptor signaling, covering both enzymes and adaptors, and will discuss their role in human disease.

FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase that is expressed almost exclusively in the hematopoietic compartment. Its ligand, FLT3 ligand (FL), induces dimerization and activation of its intrinsic tyrosine kinase activity. Activation of FLT3 leads to its autophosphorylation and initiation of several signal transduction cascades. Signaling is initiated by the recruitment of signal transduction molecules to activated FLT3 through binding to specific phosphorylated tyrosine residues in the intracellular region of FLT3. Activation of FLT3 mediates cell survival, cell proliferation, and differentiation of hematopoietic progenitor cells. It acts in synergy with several other cytokines to promote its biological effects. Deregulated FLT3 activity has been implicated in several diseases, most prominently in acute myeloid leukemia where around one-third of patients carry an activating mutant of FLT3 which drives the disease and is correlated with poor prognosis. Overactivity of FLT3 has also been implicated in autoimmune diseases, such as rheumatoid arthritis. The observation that gain-of-function mutations of FLT3 can promote leukemogenesis has stimulated the development of inhibitors that target this receptor. Many of these are in clinical trials, and some have been approved for clinical use. However, problems with acquired resistance to these inhibitors are common and, furthermore, only a fraction of patients respond to these selective treatments. This review provides a summary of our current knowledge regarding structural and functional aspects of FLT3 signaling, both under normal and pathological conditions, and discusses challenges for the future regarding the use of targeted inhibition of these pathways for the treatment of patients.

Resistance to therapy remains a major cause of cancer treatment failures, resulting in many cancer-related deaths. Resistance can occur at any time during the treatment, even at the beginning. The current treatment plan is dependent mainly on cancer subtypes and the presence of genetic mutations. Evidently, the presence of a genetic mutation does not always predict the therapeutic response and can vary for different cancer subtypes. Therefore, there is an unmet need for predictive models to match a cancer patient with a specific drug or drug combination. Recent advancements in predictive models using artificial intelligence have shown great promise in preclinical settings. However, despite massive improvements in computational power, building clinically useable models remains challenging due to a lack of clinically meaningful pharmacogenomic data. In this review, we provide an overview of recent advancements in therapeutic response prediction using machine learning, which is the most widely used branch of artificial intelligence. We describe the basics of machine learning algorithms, illustrate their use, and highlight the current challenges in therapy response prediction for clinical practice.

WNT/β-catenin signaling is a highly complex pathway that plays diverse roles in various cellular processes. While WNT ligands usually signal through their dedicated Frizzled receptors, the decision to signal in a β-catenin-dependent or -independent manner rests upon the type of co-receptors used. Canonical WNT signaling is β-catenin-dependent, whereas non-canonical WNT signaling is β-catenin-independent according to the classical definition. This still holds true, albeit with some added complexity, as both the pathways seem to cross-talk with intertwined networks that involve the use of different ligands, receptors, and co-receptors. β-catenin can be directly phosphorylated by various kinases governing its participation in either canonical or non-canonical pathways. Moreover, the co-activators that associate with β-catenin determine the output of the pathway in terms of induction of genes promoting proliferation or differentiation. In this review, we provide an overview of how protein phosphorylation controls WNT/β-catenin signaling, particularly in human cancer.

Therapy directed against oncogenic FLT3 has been shown to induce response in patients with acute myeloid leukemia (AML), but these responses are almost always transient. To address the mechanism of FLT3 inhibitor resistance, we generated two resistant AML cell lines by sustained treatment with the FLT3 inhibitor sorafenib. Parental cell lines carry the FLT3-ITD (tandem duplication) mutation and are highly responsive to FLT3 inhibitors, whereas resistant cell lines display resistance to multiple FLT3 inhibitors. Sanger sequencing and protein mass-spectrometry did not identify any acquired mutations in FLT3 in the resistant cells. Moreover, sorafenib treatment effectively blocked FLT3 activation in resistant cells, whereas it was unable to block colony formation or cell survival, suggesting that the resistant cells are no longer FLT3 dependent. Gene expression analysis of sensitive and resistant cell lines, as well as of blasts from patients with sorafenib-resistant AML, suggested an enrichment of the PI3K/mTOR pathway in the resistant phenotype, which was further supported by next-generation sequencing and phospho-specific-antibody array analysis. Furthermore, a selective PI3K/mTOR inhibitor, gedatolisib, efficiently blocked proliferation, colony and tumor formation, and induced apoptosis in resistant cell lines. Gedatolisib significantly extended survival of mice in a sorafenib-resistant AML patient-derived xenograft model. Taken together, our data suggest that aberrant activation of the PI3K/mTOR pathway in FLT3-ITD-dependent AML results in resistance to drugs targeting FLT3.