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Page 12 of 19 Cordover et al. J Cancer Metastasis Treat 2020;6:45 I http://dx.doi.org/10.20517/2394-4722.2020.101

CXCL13, which are associated with tumor metastasis and migration [79,81] . Moreover, PI3Kβ-selective
inhibitors are promising for the treatment of a group of solid tumors. PI3Kβ inhibitors were shown to
inhibit tumor cell growth in PTEN-null advanced solid tumors. Nevertheless, prolonged treatment of
PTEN-deficient cancers with PI3Kβ inhibitors may cause tumor cells to shift their dependency from the
[82]
PI3Kβ to the PI3Kα isoform .

mTOR inhibitors
[83]
mTOR was originally identified to be a target for the anti-fungal agent rapamycin . The dysregulation
of mTOR is shown to promote cancer growth and metastasis and mTOR thus serves as an important
therapeutic target. mTOR regulates basic physiological processes and is frequently mutated in cancers.
mTOR is the central component of both the mTORC1 and mTORC2 complexes. Both complexes differ
in their components, substrate specificities, and subcellular localization. Aberrant mTOR signaling can
be activated in various ways in cancer. First, mutations in the mTOR gene or in the genes that encode
components of the mTORC1/2 complexes can lead to constitutive mTOR signaling. In addition, gain-of-
function mutations in upstream oncogenes or loss-of-function mutations in upstream tumor suppressors
contribute to unregulated mTOR signaling . Rapamycin, the compound from which mTOR gets its name,
[84]
was the first agent that was discovered to bind mTOR. It was shown to bind and inhibit mTORC1, but due
to its low solubility and poor pharmacokinetics, it is unsuitable for treating human cancers. As a result,
several rapamycin analogs, “rapalogs”, have been discovered. The rapalogs everolimus and temsirolimus
are prescribed to treat advanced renal cell carcinoma and breast cancer. It is evident that everolimus and
temsirolimus exert tumor-suppressive effects in vivo, but the benefits of such agents in the clinic is only
moderate. The limited clinical success of rapalogs is a result of the incomplete inhibition of mTOR and the
development of acquired resistance in tumors. Nonetheless, clinical trials to determine the efficacy and
breadth of rapalogs in different cancers is ongoing .
[85]

In order to more completely suppress mTOR, ATP-competitive mTOR inhibitors have been developed to
target both mTORC1 and mTORC2. Many of these ATP-competitive inhibitors target both mTOR and
PI3K. In various cases, the dual inhibition of PI3K and mTOR is seen to be more effective than targeting
either protein alone. For instance, in a recent study the effectiveness of the ATP-competitive PI3K/mTOR
dual inhibitor BEZ235 in the treatment of drug-resistant gastric cancers was assessed. BEZ235 inhibits
multiple class I PI3K isoforms and mTORC1/2 activity. Unlike mTOR inhibitors alone, BEZ235 was shown
to decrease AKT activity in vitro, contributing to its potent anticancer effects. However, it is important to
note that although BEZ235 has significant anti-tumor activity, it is shown to enhance ERK activity through
mTORC2. The use of BEZ235 in combination with MEK inhibitors is seen to prevent ERK overactivation
and to significantly inhibit cell growth [86,87] . Similarly, another study reported the use of a newly developed
PI3K/mTOR dual inhibitor, CMG002, in chemoresistant ovarian cancer. CMG002 was shown to suppress
[88]
cancer cell proliferation and to induce apoptosis and G1 arrest in drug-resistant ovarian cancer cells . As
such, both BEZ235 and CMG002 as single agents serve as promising strategies in cancer treatment. Further
work is being done to study the effects of dual PI3K/mTOR inhibitors in combination with inhibitors that
target the Ras/Raf/MEK/ERK pathway.

THE PAK FAMILY
The Pak family of protein kinases are important signaling proteins implicated in many cellular functions
[89]
including cell proliferation, migration, and cytoskeletal organization . They can mediate a response to
RTKs and other activators. They can lead to activation of MAP kinases and other signaling pathways. They
were first identified as protein kinases that bind and are activated by the Rho GTPases Rac and Cdc42 (Fig. 4).
The Pak family consists of 6 members. These include group A (Paks 1, 2, and 3) and group B (Paks 4, 5,
[89]
and 6) . The Paks have several different domains, including a GTPase binding domain (GBD), a short
sequence which can bind to the Rho GTPases Cdc42 and Rac, and a serine/threonine kinase domain.