atly enhanced apoptosis and reduced the invasive potential of these GBM resistant cells. The correlation between IGF 1R activation and acquired resistance to EGFR blockade has been demonstrated also for breast and prostate cancer NVP-AUY922 HSP-90 inhibitor cell lines. MCF 7 breast cancer cells with acquired resistance to tamoxifen and to gefitinib exhibit elevated levels of IGF IR, PKC and AKT, but no detectable basal phospho EGFR activity. Treatment of these cells with the specific IGF IR inhibitor AG1024 resulted in a significant growth inhibition and in a reduced migratory capacity. Similarly, a gefitinib resistant variant of androgen independent human prostate cancer cell line DU145 activates increased signaling via the IGF 1R pathway. Importantly, IGF 1R overexpression inversely correlates with response to anti HER2 MAb Trastuzumab in breast cancer cells.
Moreover, a physical association between HER2 and IGF IR has been found in tamoxifen and gefitinib BSI-201 IND-71677 resistant MCF 7 cells. Similarly, a heterodimerization of EGFR and IGFR has been recently reported as main determinant of erlotinib resistance in NSCLC cell lines. Tortora et al. Page 4 Drug Resist Updat. Author manuscript, available in PMC 2008 September 23. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript 2.3. Independent or constitutive activation of intracellular molecular effectors downstream to the target protein Activation of signalling pathways downstream of EGFR, is caused by gene amplification, overexpression of downstream effectors, such as PI3K/AKT, and/or loss or inactivating mutations of phosphatase and tensin homologue, a lipid phosphatase that inhibits the PI3K/AKT pathway, all leading to a persistent activation of the PI3K/AKT and MAPK pathways and consequent development and maintenance of an EGFR resistant phenotype.
A hyperactive PI3K/AKT pathway has been also found in tumour samples from advanced gastric cancer or colorectal cancer patients failing EGFR targeted therapy. Loss or reduction of PTEN expression occurs in some advanced cancers including GBM, melanoma, endometrial, breast, ovarian, renal cell, thyroid, and a small subset of NSCLC. The reconstitution of PTEN in PTEN null cells is able to repress AKT and to inhibit tumour growth via induction of apoptosis or inhibition of cell proliferation. The lack of PTEN function in cancer cells is responsible for the resistance to HER2 inhibitor Trastuzumab and to EGFR TK inhibitors.
For instance, patients with PTEN deficient breast cancers have significantly poorer responses to Trastuzumab based therapy than those with normal PTEN. Human breast cancer MDA 468 cells, lacking a functional PTEN protein, are relatively resistant to gefitinib treatment display an AKT activity independent from EGFR signals. The introduction of a functional PTEN results in a restored gefitinib induced AKT inhibition and inhibition of cell growth and apoptosis. These effects have been reproduced also with the other EGFR inhibitors, erlotinib and cetuximab. Intriguingly, the dual EGFR and HER2 inhibitor lapatinib has recently shown activity in inflammatory breast cancer patients overexpressing HER2 regardless of PTEN status. Other signaling downstream to EGFR producing a constitutively activated pathway are Src, a non receptor tyrosine kinase whose elevated levels correlate with poor prognosis in solid tumours and MAPK, whose persistent activation is associated with resistance to EGFR inhibitors in NSCLC and breast cancer. Also the signal tra