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Cordover et al. J Cancer Metastasis Treat 2020;6:45 I http://dx.doi.org/10.20517/2394-4722.2020.101 Page 11 of 19

All known major effectors of the PI3K/AKT/mTOR pathway are frequently mutated in cancer. As
previously mentioned, PI3K depends upon RTKs for its activation. Because the majority of PI3K is inactive
in the cytoplasm, even miniscule changes in RTK activity can lead to overactivation of PI3K. For instance,
mutations that lead to increased activation of EGFR (ERBB1) and HER2 are associated with cancers with
[68]
aberrant PI3K pathway signaling . In addition, activating mutations in the platelet derived growth factor
(PDGFRα) RTKs are found to be present in several cancers, including gastrointestinal stromal tumors and
mammary carcinomas [69,70] . Further, activating missense mutations in PIK3CA, the gene that encodes for the
p110α catalytic subunit of PI3K, are found in a wide variety of cancer types. Tumor suppressor phosphatase
and tensin homolog (PTEN) regulates and represses PI3K activity by the dephosphorylation of secondary
messenger PIP3. PTEN, however, is found to be mutated in several tumors which results in the constitutive
activation of PI3K. Activating mutations in PI3KCA and inactivating mutations in PTEN are often found
to coexist in many cancers, such as breast cancer and colon cancer. Amplification of AKT is also seen in
cancer as a result of mutations in the AKT1 gene [71,72] . Lastly, there are various cancer-related mutations in
[73]
the MTOR gene. These mutations affect the activity and assembly of both mTORC1 and mTORC2 .

PI3K inhibitors
There are three main classes of PI3K inhibitors - pan-PI3K inhibitors, isoform specific PI3K inhibitors, and
dual PI3K/mTOR inhibitors. Several pan-class I PI3K inhibitors are currently in clinical development .
[74]
Pan-class I PI3K inhibitors exert inhibitory effects against each isoform of PI3KCA, the gene that encodes
for p110α, the catalytic domain of PI3K. Buparlisib, for instance, binds to the ATP binding site of the lipid
domain of PI3K and exhibits potent activity in cancers with PI3KCA activating mutations that are found in
a wide range of human cancers. In addition, copanlisib, another pan-PI3K inhibitor, also shows significant
anti-tumor activity in cancers with PI3KCA mutations and in cancers with HER2 overexpression. Pan-class
I PI3K inhibitors have shown anticancer effects when administered as single agents. Nonetheless, there
are multiple side effects that limit the efficacy of class-I inhibitors, such as hyperglycemia and fatigue [75-77] .
Further, isoform specific PI3K inhibitors have advantages over pan-PI3K inhibitors because they only bind
to one isoform of PI3K. There are four class-I PI3K isoforms (PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ), and each
isoform plays non-redundant roles in particular tumor types. Hence, by targeting one isoform, undesirable
[78]
side effects can be limited .
As previously mentioned, mutations in the PI3KCA gene are recurrent in solid tumors. There are several
selective and highly specific inhibitors that target the PI3Kα isoform, which is composed of the p110α
catalytic subunit encoded by PI3KCA. Preclinical studies have shown that HER2- and KRAS-driven tumors
rely on PI3Kα for tumor survival. Hence, the inhibition of this isoform by selective PI3Kα inhibitors acts as
a promising therapeutic target. These inhibitors have been shown to have potency against wild-type PI3Kα
and E545K and H1047R gain-of-function mutants. Such inhibitors, such as NVP-BYL719, are shown to
block the phosphorylation of AKT, which is highly dependent on p110α activity. In addition, isoform-
specific PI3Kα inhibitors are shown to decrease glucose consumption and blood supply to cancer cells,
contributing to their anti-tumor effects. As such, further studies are being carried out to determine whether
using isoform-specific PI3Kα inhibitors in combination with other agents enhances tumor regression [79,80] .

In addition to PI3Kα, targeting the PI3Kδ isoform may be beneficial for certain cancers. PI3Kδ is largely
seen in leukocytes and serves as an important target for cancer and immune-related diseases. As it is
downstream to several B-cell receptors, PI3Kδ plays an integral role in B-cell signaling and is seen in
B-cell related malignancies. Mutations in the PI3KD gene have not been found in patients with chronic
lymphocytic leukemia, but previous studies report that increased PI3K activity is highly dependent on
PI3Kδ isoform as observed in these cancers. PI3Kδ selective inhibitor CAL101 blocks constitutive PI3K
signaling that confers cancer cell survival, such as the phosphorylation of AKT and ERK1/2. Notably,
CAL101 has also been demonstrated to reduce the levels of circulating chemokines CCL3, CCL4, and