Drug resistance continues to be a significant problem associated with many cancer therapies. Of the 565,650 cancer deaths projected in the U.S. in 2008, a large percentage will involve patients who develop resistance to chemotherapeutics, radiation therapy, biologic agents, and targeted therapy regimes.
In recent months, the role of the PI3K/Akt/mTOR signaling pathway in chemoresistance and cancer cell development has been the subject of multiple research efforts. As a result, new levels of attention have been focused on this pathway as a target in disease progression and drug development.
These research efforts have yielded novel insights into the role of the PI3K/Akt/mTOR pathway as a potentially promising target to reverse resistance to many leading cancer therapeutics. Recent research also indicates that Akt-activation inhibition may play a role in the development of HIV therapies.
Treatment failure due to chemoresistance can occur for several reasons. One common cause is cell mutation, in which cancer cells not initially killed by chemotherapy mutate and become resistant to the chemotherapeutic. Gene amplification, the replication of a gene that decreases the effectiveness of a particular chemotherapeutic, is another common cause of chemoresistance.
In other cases, cancer cells may counter the influx of a chemotherapeutic by draining the drug from cells, deactivating the protein that transports the drug across cell walls, restoring DNA breaks, or developing some other mechanism to deactivate the drug. Physicians often prescribe chemotherapeutics in combination to avoid development of resistance to one agent. Developed resistance to one drug, however, often leads to resistance to other chemotherapeutics.
Activation of protein kinase B (PKB or Akt), a key component of the PI3K signaling pathway, is known to promote cancer cell growth and survival as well as resistance to therapy. Akt pathway activation is often correlated with loss of PTEN (phosphatase and tensin homolog deleted on chromosome ten) function.
PTEN normally helps promote and regulate cell-division cycles, inhibiting uncontrolled cell growth by signaling cells to stop dividing and die. As part of this regulating function, PTEN suppresses activation of the PI3K/Akt/mTOR pathway. Loss of PTEN function can lead to hyperactivation of Akt, which has been linked to inhibition of apoptosis, a higher risk of cancer relapse, and increased resistance to widely used cancer therapeutics including trastuzumab and cisplatin.