Wnt signaling regulates several cellular processes, including differentiation, proliferation, and stem cell pluripotency. Mutations in Wnt signaling are known to lead to tumor initiation and progression. Wnt/ β-catenin signaling is dysregulated in breast cancer, where it has been shown to mediate oncogenic progression. In this review, the canonical and non-canonical pathways of Wnt/ β-catenin signaling, and their regulation of breast cancer oncogenesis and progression are described. During the last decade, several small molecules and natural compounds have shown to interfere with Wnt signaling and demonstrate potential as Wnt-targeting therapeutic agents. This review also highlights these molecules, some of which are in clinical trials. Finally, strategies of using these molecules in combination therapies with other drug agents are discussed.

CXCR4 is a Gi-coupled chemokine receptor involved in chemotaxis (directed migration) of tumor and stromal cells into the primary tumor and the prometastatic niche that are enriched in CXCL12. In breast cancer, cell surface CXCR4 levels and activity are upregulated and play an important role in local invasion and metastasis. During cancer progression, the CXCL12-CXCR4 axis orchestrates infiltration of endothelial cells and a variety of leukocytes to drive an immunosuppressive tumor microenvironment (TME). When CXCL12 from the TME activates plasma membrane-resident CXCR4 in tumor and stromal cells, a variety of pathways are activated involving signaling modules such as PI3K-AKT, MEK-ERK, and c-Sr- -p130CAS-paxillin. This triggers a wide variety of cellular processes that drive breast cancer progression, chemoresistance, and metastasis. This provides an opportunity to intervene and target these signaling axes or nodes in clinical trials to antagonize tumor growth metastasis. Finally, careful selection of targeted therapies in combination with the standard of care therapy should be selected judiciously for each patient (precision medicine) with the aim of improving the longevity with minimal toxicity to metastatic breast cancer patients.

Epidermal growth factor receptor (EGFR) expression regulates cancer cell proliferation, survival, and metastatic potential and is associated with the majority of human carcinomas, including colorectal carcinoma. The relationship between EGFR expression and its prognosis in cancer patients, however, has not been proven in clinical settings. Various preclinical studies suggest that the oncogenic potential of EGFR is associated with levels of EGFR ligands. Mutations in EGFR family ligands and their receptors are characteristic of many different kinds of tumors. Therefore, this signaling axis is an attractive target for the development of targeted therapies. Various small molecule inhibitors and antibodies are in clinical trials that specifically target EGFR.

Here, we will discuss the current literature’s attempts to identify markers, which contribute resistance and sensitivity to small molecule EGFR inhibitors. Moreover, we will summarize the role of EGFR in the development of colon cancer. We will discuss the mechanistic basis for EGFR interaction with various molecules, its consequences for biology, and its prospective importance as a target for colon cancer therapy.

Hepatocellular carcinoma (HCC) is the most common liver cancer and the leading cause of cancer-related deaths. Advanced HCC has a poor prognosis with limited treatment option. Chronic liver diseases and cirrhosis are the main risk factors for the development of HCC. Phosphoinositide 3-kinase PI3K/AKT/mTOR, intracellular mediators play a very important role in the development and progression of HCC. This signaling pathway is frequently activated in HCC patients. Therefore, signaling pathways have become the main source of targets for new treatments in HCC patients.

In our chapter, we will discuss the role of PI3K/AKT/mTOR signaling pathway in the pathology of HCC and provide an update on the preclinical and clinical approaches for the development of various molecular agents targeting this proliferation/survival pathway, which include various PI3K/Akt/mTOR inhibitors and other agents for the treatment of HCC.

Pancreatic cancer remains one of the most clinically challenging cancer despite the advancement in molecular characterization of this disease. Malignancy of this disease is characterized by the constitutively activated mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway is activated by growth factors, mitogens, hormones, cytokines and environmental factors. Activated MAPK induces expression of downstream genes and regulates cell proliferation, survival, differentiation, motility, receptor signaling, senescence and transport. Activation of MAPK in pancreatic cancer is associated with a poor prognosis and results in limited treatment options. This poor prognosis elicits a need for the development of effective therapeutic measures to treat and improve pancreatic cancer patient survival. MAPK targeted pancreatic cancer therapy has been developed in the last few decades with the use of a number of inhibitors. Inhibitors of RAS, MEK1/2 and ERK1/2 are the main drugs used pre-clinically and in clinical settings of pancreatic cancer treatment. Although these inhibitors have shown some clinical benefits, extensive research on the development of new MAPK signaling pathway inhibitors for the treatment of pancreatic cancer is warranted.

NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a rapid-acting transcription factor. It is present in almost all cell types and is one of the primary responders to several stimuli such as stress, cytokines, radiation, chemotherapeutic drugs, bacterial, and viral antigens. Aberrant regulation and activation of NF-κB have been implicated in several cancers, inflammatory and autoimmune disorders, viral infections, and erroneous immune system development. This chapter summarizes the role of NF-κB activation specifically in hematological malignancies and various strategies developed for its potential pharmacological intervention to abrogate the process of carcinogenesis.

The Bruton’s tyrosine kinase (BTK) is a non-receptor protein-tyrosine kinase (PTK) required for the growth and differentiation of B-lymphocytes, which play a critical role in the progression of numerous neoplasms. Therefore, BTK has emerged as an exciting and attractive target for inhibition of hematological malignancies. Various BTK inhibitors have already proved remarkable tumor suppressing ability in clinical studies. Ibrutinib was the trail blazing BTK inhibitor that first showed exceptional tumor inhibition in patients, this molecule showed excellent response in refractory/relapsed (R/R) conditions with high-risk genetic lesions patients, particularly among chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Based on ibrutinib’s efficacy and tolerability, in 2016, the Food and Drug Administration (FDA) approved it as a first-line treatment for CLL patients. Ibrutinib occupies the ATP-binding active site of BTK, making salt bridges within the hinge that connects the two enzyme lobes followed by the unsaturated acrylamide group of ibrutinib covalently bonding with the BTK cysteine 481 residue to irreversibly form an inactive adduct. However, ibrutinib’s irreversible binding mechanism leads to acquired resistance to the medication. Both resistance arising due to mutations that impair the affinity of ibrutinib for BTK and the undesirable side effects of the drug have led to the development of numerous second-generation inhibitors. The efficacy and specificity of novel BTK inhibiting agents such as Acalabrutinib, ONO/GS-4059, KS99, and other small molecules have substantiated solutions to ibrutinib’s shortcomings. The detailed role of BTK signaling pathways, and its cross-talk between other signaling pathways, the significance of BTK inhibition in hematological malignancies, and the current progress in the discovery of small molecule BTK inhibitors are presented in this chapter.

Acute myeloid leukemia (AML) is a cancer of blood and bone marrow, caused by abnormal production of white blood cells. According to the recent 2020 statistics, an estimated number of 19,940 people in the United States will be diagnosed with AML. The hematologic tumor microenvironment plays a critical role in the progression of AML. Emerging evidence indicates that chemotherapy resistance and disease relapse are linked through the signaling pathways associated with the tumor microenvironment in AML. The leukemia cells communicate with the other noncancerous cells of the tumor microenvironment through small vesicles that are within the size of 30-120nm called exosomes, a type of extracellular vesicles. Exosomes contain genetic information in their cargo, in the form of either protein, DNA, or noncoding RNAs and communicate to the distinct cells through various signaling pathways. The c-Myc oncogenic transcription factor protein is a master regulator of oncogenic signaling pathways in various cancers, including AML. C-Myc has been associated with the development of therapy resistance in AML, representing a key target. The interconnection between exosomes, tumor microenvironment, c-Myc and the development of progression, therapy resistance are discussed in this chapter and thus, represents a fundamental knowledge of the recent advances in cancer signal transduction and therapy.