Targeting PI3K Signaling in Combination Cancer Therapy

Combination therapies increase the efficacy of PI3K inhibitors. The efficacy of PI3K combination strategies will require targeting the tumor and the stroma (immune cells, vasculature, lymphatic system, tumor-associated fibroblasts, mesenchymal stem cells, and adipocytes). Multiple targeted therapies with drugs inhibiting all PI3Ks in the clinic demonstrate high toxicities and difficulties in predicting the targeted patient populations. PI3K-related mutations detected in circulating tumor DNA may be used as a predictive biomarker of response. Targeting upstream phosphatidylinositol-3-kinases (PI3Ks) in the PI3K/Akt/mTOR pathway appears to be a promising therapy in solid cancers; however, first early clinical trials with PI3K inhibitors in monotherapy have been disappointing. A massive array of preclinical and clinical trials are currently evaluating combinations of PI3K inhibitors in targeted therapies. These combinations include co-treatments with drugs directed against other intra-/extracellular signaling molecules, nuclear hormone receptors, DNA damage repair enzymes, and immune modulators. We review the literature and pinpoint mechanisms of action in different genomic and organ contexts. Combinatorial approaches are potentially superior to monotherapies and should become alternative clinical strategies to treat cancer patients. Targeting upstream phosphatidylinositol-3-kinases (PI3Ks) in the PI3K/Akt/mTOR pathway appears to be a promising therapy in solid cancers; however, first early clinical trials with PI3K inhibitors in monotherapy have been disappointing. A massive array of preclinical and clinical trials are currently evaluating combinations of PI3K inhibitors in targeted therapies. These combinations include co-treatments with drugs directed against other intra-/extracellular signaling molecules, nuclear hormone receptors, DNA damage repair enzymes, and immune modulators. We review the literature and pinpoint mechanisms of action in different genomic and organ contexts. Combinatorial approaches are potentially superior to monotherapies and should become alternative clinical strategies to treat cancer patients. a predictive biomarker (in blood or in tumor tissue for example) helps to identify which patients will benefit from treatment. A pharmacodynamic biomarker is a molecular indicator of drug effect on the target. small DNA fragments in blood. Tumor-derived DNA present in circulating DNA, also known as circulating tumor DNA (ctDNA), provides a less invasive approach to diagnose cancers, monitor chemotherapy-resistant mutations, and overcome the problem of tumor heterogeneity; this is the basis of the concept of 'liquid biopsy'. treatments targeting androgen and estrogen in cancer are based on their involvement in cancer initiation and progression. These endocrine hormones act by binding to nuclear receptors, which then translocate to the nucleus and activate the transcription of target genes to promote cancer cell survival and proliferation. These receptors may also have so-called non-genomic actions, corresponding to rapid signaling from the plasma membrane or the cytoplasm. Androgen deprivation therapy (enzalutamide, abiraterone acetate) is the standard treatment for metastatic prostate cancer. Treatment of estrogen receptor (ER)-positive tumors (∼80% of all breast cancers) is based on hormone therapy. the inhibition of two signaling enzymes possibly activated by the same membrane receptor but activated in parallel by a specific cascade of events. the inhibition of two signaling enzymes that are successively activated within the same pathway, such as PI3K and its indirect downstream target mTOR. Ras proteins [wild-type (WT) and oncogenic] and receptor tyrosine kinases (RTKs) are the upstream regulators of MAPK pathway. Ras proteins have multiple downstream targets such as Raf kinases that activate MEK1/2, which catalyzes the activation of extracellular signal-regulated kinases 1/2 (ERK1/2). Activated ERK1/2 further phosphorylates a series of downstream targets involved in cellular processes. neo-adjuvant therapy is given before the surgical procedure in a curative attempt; it may be given to attempt to shrink the cancer such that the surgical procedure may not need to be as extensive. Adjuvant therapy is given to limit residual cells that may be present after the tumor is removed by surgery, preventing cancer recurrence. Palliative therapy is given specifically to address symptom management. It aims to prolong both overall survival and quality of life through disease control. the identification of a group of patients with shared biological characteristics; clinical trials are used to select the optimal management for different groups and to identify the best therapeutic strategy for each patient. also known as de novo resistance, drug resistance that is present in tumor cell before any treatment; these subpopulations of clones emerge as dominant after treatment. members of the RTK family are located at the cell membrane and present intrinsic tyrosine kinase activity. After extracellular ligand binding, and homo- or heterodimerization with other members of RTK family, they induce receptor autophosphorylation and activation of several downstream pathways including the PI3 K pathway. The two major members of this family involved in oncogenicity are EGFR and HER2. Therapeutic strategies for RTK include (i) recombinant humanized antibodies (such as trastuzumab and pertuzumab targeting HER2), (ii) a tyrosine kinase inhibitor (TKI; lapatinib), or (iii) an antibody–drug conjugate (ADC), T-DM1. Monoclonal antibodies target the extracellular domain whereas TKIs target their intracellular tyrosine kinase domain. the acquisition of genetic and non-genetic alterations within the cancer cells under treatment pressure (such as alterations to drug metabolism, increased drug efflux, decreased drug uptake, modification of the drug targets, amplification of the targeted protein). the use of drugs to target specific molecules involved in the growth and spread of cancer cells.