eutic strategy proven to be successful in different types of cancer. 3.2. Combination of EGFR and mTOR inhibitors The mammalian target of rapamycin is a serine/threonine kinase downstream mediator in the PI3K/AKT signaling pathway that plays a critical role in regulating cell proliferation, growth, survival, invasion and angiogenesis. Moreover, activation GDC-0449 879085-55-9 of mTOR can occur independently from EGFR signaling trough non PI3K/AKT pathways. Everolimus and temsirolimus are rapamycin analogues that selectively inhibit mTOR function and have demonstrated promising activity in early clinical trials. Because EGFR and mTOR functions control linked signaling pathways, the combination of their specific inhibitors may represent a rational therapeutic strategy.
Gefitinib and rapamycin in combination synergistically inhibit the growth of renal cell carcinoma lines, especially those without von Hippel Lindau mutations. Rapamycin is able to enhance the sensitivity of other TKI such as erlotinib, even in PTEN deficient tumour cells. Combined EGFR/mTOR kinase inhibition inhibits PI3K pathway signaling, promoting cell PF-04217903 956905-27-4 death in PTEN deficient tumour cells. Early clinical trials in patients with recurrent GBM have shown that either gefitinib or erlotinib in combination with the mTOR inhibitor sirolimus provide an encouraging percentage of objective response. New multi targeted agents directed against EGFRdependent pathways and mTOR have been designed: the single agent PI 103 possess the unique capability of simultaneously blocking both PI3K/AKT and mTOR signaling, showing significant activity in GBM xenografts.
Based on this preclinical evidence clinical trials of temsirolimus or everolimus in combination with EGFR TKI are now ongoing. Tortora et al. Page 7 Drug Resist Updat. Author manuscript, available in PMC 2008 September 23. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript 3.3. Inhibition of signaling from EGFR and Ras The critical role of Ras in the transduction machinery of signaling from cell surface receptors to downstream molecular effectors and its relationship with development of resistance against EGFR antagonist explain the importance of Ras as a target of novel anticancer combinations. Furthermore, Ras mutations induce its constitutive activation, producing persistent stimulation of tumour cell proliferation and inhibition of apoptotic cell death.
It has been proposed that inhibition of Ras/Raf/MAPK signaling with farnesyl transferase inhibitors may enhance the anti tumour activity of EGFR inhibitors. Consistent with this hypothesis, AZD3409, a novel prenyl inhibitor active against both farnesyl transferase and geranyl geranyl transferase, has shown potent growth inhibitory activity in tumour cells resistant to EGFR antagonists and synergism in combination with gefitinib. Combination of gefitinib with the FTI SCH66336 cooperatively inhibited the growth of NSCLC cells. 3.4. Multi target agents targeting multiple signalling pathways A multi target inhibition approach that combines inhibitors of angiogenesis and the Ras/Raf/ MAPK pathway and EGFR has been examined. Sorafenib is an oral multikinase inhibitor able to block several different targets, such as Raf kinase and VEGFR and PDGFR TKs. Combining EGFR antagonists and sorafenib appears, at least theoretically, an interesting approach, able to inhibit growth factor signaling upstream at the level of EGFR and downstream at the level of Raf kinase. Moreover, inhibition of