1 Otorhinolaryngology Department, Nice General Hospital; 2 Oncopharmacology Unit, Centre Antoine-Lacassagne, Nice, France
*Correspondence to: Dr G. Milano, Oncopharmacology Unit, Centre Antoine-Lacassagne, 33, Avenue de Valombrose, 06189 Nice Cedex 2, France. Tel: +33-4-92-03-15-53; Fax: +33-4-93-81-71-31; Email: gerard.milano{at}nice.fnclcc.fr
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Abstract |
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Key words: Cetuximab, epidermal growth factor receptor, Iressa, targeted treatment, tyrosine kinase inhibitor
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Introduction |
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EGFR pathway |
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Pharmacology of EGFR targeting |
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Several deletions and mutations of EGFR have been reported so far. The most common mutation, leading to a deletion of the extracellular domain, is the type III mutation (EGFRvIII [18]). EGFRvIII is unable to bind EGF. The presence of EGFRvIII has been reported in various malignancies including lung, breast and especially glioblastomas [19
23
]. The ligand-independent mutant protein is constitutively phosphorylated [18
, 24
, 25
]. Thus, the presence of a given proportion of EGFRvIII may influence the efficacy of EGFR targeting. Of note, recent work by Heimberger et al. [26
] has shown that ZD1839 is active against a brain tumoral model expressing EGFR, but the presence of EGFRvIII confers resistance to this TKI. To our knowledge, there is no clear understanding of the relative action of C225 on wild-type EGFR and EGFRvIII. It would be interesting, therefore, to undertake a close examination of this aspect of the C225 mechanism of action. In a recent study, Mishima et al., using mAG806, a monoclonal antibody that recognizes EGFRvIII, observed, at experimental level, significant efficacy against aggressive gliomas that overexpress EGFRvIII [27
].
The presence of EGFR ligands, especially EGF and TGF, may, at least theoretically, play opposite roles according to the type of EGFR targeting. Indeed, EGFR natural ligands may compete with the binding of mAbs to the receptor target. On the other hand, they may confer more dependency to the targeted cell through the activation of EGFR pathway and thus favor the activity of EGFR TKi. Recently published experimental data seem to support this view. Wakeling et al. [28
] reported on ZD1839 IC50 values in KB cells which were, on average, more than 100-fold lower in the presence of EGF compared with control cells. Liu et al. [29
] noted that the apoptotic change induced by C225 was remarkably reduced when EGF was added to the culture medium. Thus, attention should also be paid to the presence of EGFR autocrine loops in tumors when conducting clinical investigations with EGFR targeted drugs.
Downstream effects following EGFR targeting
The outcome of EGFR targeting is characterized by the disruption of a number of cellular processes that mirror the physiological consequences of EGFR signal transduction at the level of cell division, apoptosis and angiogenesis. Regarding the impact on cell division, C225 has been shown to slow down cell division up to G1 arrest with changes in molecular actors controlling cell cycle checkpoints [30, 31
]. Similar observations were recently reported with ZD1839 [32
]. It has been shown that both C225 [33
] and ZD1839 [34
] are able to modify the cellular levels in Bax and Bcl-2 underlying the pro-apoptotic impact of EGFR targeting. Of note, Liu and Fan [35
] reported that M225 activated the initiation of caspase-8. The possibility that M225 may interact with membrane-located death receptor was, however, ruled out by the same group of investigators [36
]. It would thus be interesting to compare the respective impacts of mAbs and TKIs on death receptor-mediated apoptosis. A negative influence of EGFR targeting on angiogenic biochemical mediators has been shown for both C225 and ZD1839; for instance, the tumoral labeling in VEGF and factor VIII was reduced in xenograft models under the influence of C225 [37
] as well as ZD1839 [38
]. Interestingly, and perhaps not sufficiently emphasized, is the fact that EGFR signal abrogation may lead to a diminution of key mechanisms in DNA repair. For instance, C225 application is followed by a reduction in the level of DNA protein kinase and its presence in the nuclear fraction [39
]. In this latter study, confocal imaging demonstrated that a significant proportion of DNA protein kinase was co-localized with EGFR in C225EGFR targeted cells. It would be of interest to determine whether the impact on DNA protein kinase following EGFR targeting by C225 is specific to EGFR inhibition by mAbs or can be extended to other anti-REGF strategies with TKIs.
EGFR targeting effects: in vitro/in vivo
In general, C225 treatment of tumor cell lines in culture resulted in a modest inhibition of tumor cell growth and proliferation. Growth inhibition, for instance, was in the 1550% range in a variety of human cancer cell lines [40, 41
]. Data from tumor xenograft studies suggest that the in vivo efficacy of C225 is markedly enhanced as compared with the effects on tumor cell lines in vitro. This is well exemplified in studies of A431 tumor cells that are highly sensitive to EGFR blockade due to high expression of EGFR. C225 treatment of A431 cells in vitro results in a modest 3040% inhibition of cell proliferation depending on the assay conditions [14
, 42
]. In contrast, C225 treatment of mice bearing A431 xenografts leads to complete tumor growth arrest and regression of well-established tumors [43
]. Such differences between in vitro and in vivo cytostatic/cytotoxic activities noted for C225 are not so marked with TKIs. ZD1839, along with other more recently developed TKIs, has shown marked in vitro and in vivo growth-inhibitory activity in a wide range of cell lines [3
, 44
, 45
]. It is thus likely that the in vivo efficacy of mAbs may be less the result of a direct impact on cell proliferation than the inhibition of tumor-related processes such as cell migration and neovascularization. On the other hand, a part of their antitumor activity could be attributed to antibody-dependent cellular cytotoxicity and/or complement-dependent cytotoxicity [46
]. Conducting experimental studies at this level would be interesting so as to more deeply elucidate the respective mechanisms of action of EGFR targeting by TKIs and mAbs.
Combination of EGFR targeting drugs and cytotoxics
Based on our current knowledge, there is no apparent distinction between TKIs and mAbs regarding their propensity to trigger, in the majority of cases, synergistic cytotoxic interactions with chemotherapeutic agents or irradiation. This synergy can be attributed, to a great extent, to the well-identified impact of EGFR targeting drugs on cell division, apoptosis, angiogenesis and DNA repair (see above). It must be stressed, however, that there are few, if any, experimental studies designed to explore thoroughly the different anticancer agents, class by class, in association with EGFR targeting drugs and using appropriate methods of analysis (the Chou and Talalay model, for instance). An exception is the study by Ciardiello et al., who undertook to combine ZD1839 and a panel of anticancer agents including platinum derivatives, taxanes, doxorubicine, VP16, topotecan and tomudex [44]. Treatments combining cytotoxic drugs and ZD1839 produced tumor growth arrests in established GEO human colon cancer xenografts while in single-agent-treated mice tumors resumed growth similar to controls. On comparable experimental bases, Sirotnak et al. [47
] reached similar conclusions when combining ZD1839 and taxanes, while associations with gemcitabine or vinorelbine led to more contrasted results. When combining gemcitabine and PKI 166, Kedar et al. [48
] found convincing evidence of supra-additivity in human renal cell carcinoma growing orthopically in nude mice. We recently reported on the association between ZD1839 and cisplatin-5-fluorouracil (5-FU) in head and neck cancer cell lines with the existence of sequence-dependent synergistic cytotoxic effects [45
]. Synergistic interaction between cisplatin and TKIs was also observed with CI-1033, an irreversible TKI [49
]. Similar observations were previously reported regarding experimental chemosensitization by EGFR blocking using mAbs, particularly C225. Thus C225 (or M225) has been shown to augment the antitumor activity of several anticancer agents (doxorubicin, cisplatin, 5-FU, gemcitabine, paclitaxel, topotecan and CPT11) in both cell cultures and human tumor xenograft model [14
, 41
, 50
54
]. Of note, the results reported by Prewett et al. [54
] demonstrated not only an enhanced antitumor activity of C225 combined with CPT11, but also that this combination was highly effective against established, CPT11 refractory colorectal tumors. Recent clinical data confirm the C225CPT11 combination as a promising therapeutic strategy in CPT11 refractory colorectal cancer [55
]. As stated above, a majority of combinations between anti-EGFR drugs and cytotoxics result in additive and supra-additive cytotoxic effects. However, it cannot be ruled out that antagonisms may also occur with drugs not covered by these experiments. Other possibilities for combinations with EGFR inhibitors may concern antisignaling molecules. A recent paper by Tortora et al. reports on in vitro and in vivo data, showing the promising synergistic antitumor activity of a combination of ZD1839 with SC-236 (Cox-2 inhibitor) and a PKA antisense [56
]. As observed with many anticancer drugs, the combination of anti-EGFR with irradiation (Rx) has led to more or less marked increases in cell cytotoxicity with both approaches including TKIs or mAbs. Thus, C225 associated with Rx markedly enhanced the in vitro and in vivo radiation response of various epidermoid cells, most of them being of human head and neck cancer origin [33
, 37
, 57
, 58
]. In the same way and more recently, the association between ZD1839 and Rx has resulted in cytotoxic increases shown both in vitro and in vivo not only in head and neck cancer cell lines [32
, 45
] but also in a variety of other human cancer cell lines, including colon, ovary, non-small-cell lung and breast origins [59
, 60
]. Thus, although this calls for further thorough investigation, it seems that radiosensitization by C225 is particularly dependent upon the presence of high EGFR levels, as is the case with cells of head tumoral and neck cancer origin. ZD1839 may radiosensitize a wider spectrum of tumor cell line from various primary sites. On the other hand, both C225 and ZD1839, when combined with Rx, led to antitumor activity which appears to derive not only from proliferative growth inhibition but also from a negative impact on angiogenesis [32
, 58
, 60
].
Mechanisms of resistance to EGFR targeting and perspectives
Surprisingly, there are currently few published studies dedicated to examining mechanisms of resistance to EGFR targeting irrespective of the anti-EGFR drug considered and the type of resistance, either intrinsic or acquired. Regarding intrinsic resistance, conclusions concerning the importance of EGFR cellular levels are highly contrasted. For instance, from a series of nine human cancer cell lines, Bos et al. observed an exponential relationship between EGFR cellular content and the growth-inhibitory effects of PD 153035, a new TKI [42]. Cells expressing the highest EGFR levels were the most sensitive to the TKI. We recently reported similar observations with ZD1839 on a series of seven human cancer cell lines expressing a wide range of EGFR levels from 388 to 33 794 fmol/mg protein [61
]. Using tumor xenografts in immunodeficient animals, Sirotnak et al. [47
] noted that the application of ZD1839 against tumors with low but highly variable EGFR levels resulted in 7080% tumor regression whilst the percentage fell to 5055% in tumors with very low EGFR levels. Regarding mAbs, Solbach et al. [62
] studied six tumor xenografts of human breast cancer origin expressing EGFR from 10 to 300 fmol/mg protein. They observed a therapeutic effect of antibody EMD 55 900 when tumors expressed EGFR above the 40 fmol/mg protein threshold. Thus, for EGFR, although some consensual findings tend to suggest a link between the level of the target and the intrinsic efficacy of the targeting drug, more studies, on a large number of cells or tumor xenografts, are still needed to establish convincing conclusions regarding EGFR levels and targeting efficacy on which clinical strategies can confidently be based.
It is obvious that not only the EGFR pathway itself but also other receptor-signaling pathways can drive cell proliferation and thus replace EGFR when this path is blocked. This opens up the possibility that there exist other intrinsic resistance mechanisms. Indeed, Chakravarti et al. [63] recently reported on primary glioblastoma cell lines with equivalent EGFR expression exhibiting a marked variability in sensitivity to AG 1478, a new TKI. Interestingly, a resistant cell line was shown to overexpress insulin-like growth factor receptor (IGFR)-1. In addition, the authors noted that co-targeting the resistant cell line with AG 1478 and an anti-IGFR-1 resulted in an enhancement of both spontaneous and radiation-induced apoptosis. Bianco et al. [64
] made the interesting observation that a cell line defective in the phosphatase PTEN was relatively resistant to ZD1839; this could be explained by the fact that the lack of PTEN potentially maintained AKT activity at a high level which is unresponsive to EGFR inhibition. Interestingly the authors demonstrated that ZD1839 induced a greater degree of apoptosis and cell cycle inhibition in cells where PTEN was transfected. Thus PTEN status should be considered as a source of variability in the sensitivity to EGFR targeting. Mechanisms of resistance to EGFR targeting may also arise from the co-expression of other EGFR family members such as HER-2. For instance, Christensen et al. [65
] have shown that the overexpression of HER-2 counteracted the ability of ZD1839 to block EGFR activity. A study by Viloria-Petit et al. [66
] suggests that, at least for the A431 cell line, variants displaying an acquired resistance to anti-EGFR antibodies can be produced in vivo. One identified mechanism, among others, was an increased angiogenic potential manifested by overproduction of VEGF by the tumoral cells. Thus, regarding resistance to anti-EGFR drugs, it is clear that specific investigations are still needed to enhance our understanding and to confirm the possible role of alternative signaling and angiogenic pathways. Such knowledge would provide strong rationale for optimal combinations between anti-EGFR agents and selected targeted drugs.
Received for publication July 3, 2003. Revision received November 24, 2003. Accepted for publication January 8, 2004.
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