Signaling Pathways in Cancer: Therapeutic Targets, Combinatorial Treatments, and New Developments

Abstract

Molecular alterations in cancer genes and associated signaling pathways are used to inform new treatments for precision medicine in cancer. Small molecule inhibitors and monoclonal antibodies directed at relevant cancer-related proteins have been instrumental in delivering successful treatments of some blood malignancies (e.g., imatinib with chronic myelogenous leukemia (CML)) and solid tumors (e.g., tamoxifen with ER positive breast cancer and trastuzumab for HER2-positive breast cancer). However, inherent limitations such as drug toxicity, as well as acquisition of de novo or acquired mechanisms of resistance, still cause treatment failure. Here we provide an up-to-date review of the successes and limitations of current targeted therapies for cancer treatment and highlight how recent technological advances have provided a new level of understanding of the molecular complexity underpinning resistance to cancer therapies. We also raise three basic questions concerning cancer drug discovery based on molecular markers and alterations of selected signaling pathways, and further discuss how combination therapies may become the preferable approach over monotherapy for cancer treatments. Finally, we consider novel therapeutic developments that may complement drug delivery and significantly improve clinical response and outcomes of cancer patients.

Keywords: PROTACS; RTK; cancer resistance; combinatorial treatments; oncogenes and tumor suppressors; signaling pathways; targeted therapies.

Figure 1

Targeted therapies for cancer treatment. In physiologic conditions, ligands bind to receptor tyrosine kinases (RTKs) at the cell membrane and induce the autophosphorylation of the RTKs’ catalytic domains and the activation of downstream effectors, e.g., p85 release and the activation of the p110 catalytic subunit within PI3K; GDPase–GTPase conversion of Ras. Activation of the PI3K and MAPK pathways initiates a series of phosphorylation events that promote cell growth and proliferation and regulate cellular differentiation. In the presence of estrogen, the estrogen receptor (ER) dimerizes and translocates into the nucleus where it activates pro-growth transcription programs. Examples of FDA-approved monoclonal antibodies and small molecule inhibitors acting on multiples molecular nodes are shown.

Figure 2

Targeted therapies directed at cell cycle and DNA damage repair pathways. Pro-growth stimuli promote the formation of the CDK4/6-cyclin D1 complex, which phosphorylates and inactivates the tumor suppressor Rb, and releases E2F. E2F then initiates a transcription program that supports G1-S phase transition. Genomic stress activates DNA damage response (DDR) mechanisms, e.g., ATM/ATR, and PARP signaling pathways, and triggers the Chk1/2-p53-p21 axis to induce cell cycle arrest, senescence, or apoptosis as a means to halt the propagation of genetic lesions. Accumulation of DNA double-stranded breaks (DSB) can be repaired by two mechanisms: (1) the error-free homologous recombination, HR; or (2) the error-prone non-homologous end-joining, NHEJ. FDA-approved PARP inhibitors, e.g., Olaparib, when used with standard treatments, can force HR repair-defective cells, such as in BRCA1 mutant cells, to activate the error-prone NHEJ pathway, leading to genomic instability beyond repair and causing cell death. BARD1 (BRCA1-associated RING domain protein 1); RIF1 (Rap1-interacting factor 1 homolog); and 53BP1 (TP53-binding protein 1).