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Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Redwood Building, Cardiff University, King Edward VII Avenue, Cardiff CF10 3XF, UK

(Requests for offprints should be addressed to H E Jones; Email: joneshe1{at}cardiff.ac.uk)

This paper was presented at the 2nd Tenovus/AstraZeneca Workshop, Cardiff (2006). AstraZeneca supported the meeting and the Welsh School of Pharmacy, Cardiff University has supported the publication of these proceedings.

	Abstract

Top Abstract Introduction Pathway switching between the... Receptor interactions Co-targeting the EGFR and... Clinical relevance Conclusion References

 
Aberrant signalling through the epidermal growth factor receptor (EGFR) plays a major role in the progression and maintenance of the malignant phenotype and the receptor is therefore a rational anti-cancer target. A variety of approaches have been developed to specifically target the EGFR which include monoclonal antibodies and small molecule tyrosine kinase inhibitors, such as gefitinib (Iressa). However, the recent clinical experience across a range of cancer types is revealing that despite the anti-EGFR agents demonstrating some anti-tumour activity, there is a high level of de novo and acquired resistance to such treatments and moreover, overexpression of the EGFR is clearly not the sole determinant of response to such therapies. Such adverse phenomena, which serve to limit the overall therapeutic impact of these new agents, implies the existence of a greater complexity involved in the regulation of EGFR signalling than was previously assumed. Indeed, evidence is accumulating which demonstrates that signalling interplay occurs between the EGFR, and the IGF-1 receptor (IGF-1R) and the review will focus on the emerging concept of growth factor pathway switching between these two receptors as a means of influencing the effectiveness of anti-EGFR agents such as gefitinib.

	Introduction

Top Abstract Introduction Pathway switching between the... Receptor interactions Co-targeting the EGFR and... Clinical relevance Conclusion References

 
For the last two decades, it has been recognised that the epidermal growth factor receptor (EGFR) is associated with many adverse features of the malignant phenotype, such as increased proliferation, decreased apoptosis, metastasis and resistance to chemo- and radiotherapy (Salomon et al. 1995, Nicholson et al. 2001). In addition, the EGFR is also overexpressed in numerous solid tumour types, including 20–30% of breast cancers, where it often heralds an aggressive cancer type and consequently, poor patient outlook. (Nicholson et al. 1993, Gee et al. 2005). Based on these observations, it was therefore a logical assumption that targeting the EGFR might result in the restoration of a more normal phenotype and hence, provide clinical benefit to patients with otherwise limited therapeutic options. With the advent of the molecular biology era, we have been recently provided with the pharmacological tools to undertake such selective receptor inhibition and agents, which include antagonistic antibodies and small molecule tyrosine kinase inhibitors, which target the EGFR have been developed (Ciardiello & Tortora 2001). Disappointingly, however, the emerging clinical experience across a range of cancer types is revealing that despite the anti-EGFR agents demonstrating some anti-tumour activity, there is a high level of de novo resistance to such treatment (Ranson et al. 2002, Schiller 2002, Gee et al. 2004, Kelly & Averbuch 2004, Rothenberg et al. 2004) where overexpression of the EGFR is clearly not a determinant of response to anti-EGFR therapies (Arteaga 2002, Saltz et al. 2004). Moreover, it has also been observed that even in responders, the acquisition of resistance and hence, disease relapse occurs fairly rapidly (Ranson et al. 2002, Schiller 2002, Kelly & Averbuch 2004, Rothenberg et al. 2004). The overall therapeutic impact of these new agents is limited by the existence of such adverse phenomena and moreover, indicates that the biology regulating EGFR signalling is far more complex than was previously assumed. Indeed, it is known that cancer cells are extremely adaptable or plastic in their ability to utilise cellular pathways which control the aspects of their physiology. For example, through overexpression of a particular receptor, such as the EGFR, they may have apparently adopted a dominant growth regulatory pathway. However, evidence is accumulating which demonstrates that they can readily switch to using alternative signalling pathways to maintain cell survival when this dominant pathway is blocked. In this light, the article will focus on the crosstalk or pathway switching that we are now recognising occurs between the EGFR and the insulin-like growth factor-1 receptor (IGF-1R), which can ultimately influence the effectiveness of anti-EGFR agents, such as the small molecule inhibitor gefitinib.

	Pathway switching between the EGFR and IGF-1R: implications for gefitinib therapy

Top Abstract Introduction Pathway switching between the... Receptor interactions Co-targeting the EGFR and... Clinical relevance Conclusion References

 
The phenomenon of growth factor pathway switching from one pathway to another has an adaptive component which may be induced by virtue of blocking the dominant growth factor receptor pathway. Indeed, early work in our laboratory indicated that blockade of EGFR signalling resulted in the enhancement of the growth promoting effects of the peptide growth factor ligands basic fibroblast growth factor and IGF-I in DU145 and PC-3 human prostate cancer cells respectively (Jones et al. 1997). More recently, we have shown that the substantial growth inhibitory effects of the EGFR-selective tyrosine kinase inhibitor gefitinib on our EGFR-positive MCF-7-derived tamoxifen-resistant breast cancer cells can easily be subverted by additionally exposing the cells to non-EGF ligands, such as heregulin-ß (Hutcheson et al. 2003) and IGF-II (Knowlden et al. 2005). The reversal of the anti-tumour effects of gefitinib by IGF-II, acting through the IGF-1R is also accompanied by a reactivation of the previously reduced activity of Akt and extracellular regulated kinase (ERK), whose signalling contributes to the re-establishment of tumour cell growth (Knowlden et al. 2005). Thus, even in the presence of a dominant growth pathway, the cancer cells are capable of responding to other growth factors which may be present, thereby compromising the anti-tumour activity of the agents, which have been designed to specifically inhibit the EGFR.

Importantly, we have shown that following blockade of EGFR signalling, switching to the IGF-1R pathway is a common mechanism to promote resistance to anti-EGFR treatment. For example, although gefitinib initially inhibited the growth of several EGFR-positive cell lines, namely DU145 prostate cancer cells and our MCF-7-derived tamoxifen- (Knowlden et al. 2003) and fulvestrant- (Faslodex) (McClelland et al. 2001) resistant breast cancer cell lines, it was seen that chronic challenge with the inhibitor resulted in the development of gefitinib-resistant variant sublines, all of which displayed an upregulation of multiple IGF-1R signalling components when compared with the parental cell line (Jones et al. 2004, 2005). This included increased production of the IGF-1R ligand IGF-II and elevated expression, and activity of the IGF-1R and increased levels of Akt activity (Jones et al. 2004, 2005). In addition, the lung cancer cell line A549, which displays a partial sensitivity to gefitinib, was also chronically challenged with the inhibitor and the resistant variant which emerged, and also showed a marked adaptive increase in the activity of elements of the IGF-1R pathway (Jones et al. 2006a). The importance of the IGF-1R signalling in these various cell types with acquired gefitinib resistance was further supported by the observation that they all demonstrated an enhanced dependency on IGF-1R signalling as they were subsequently more sensitive to growth inhibition by IGF-1R-selective tyrosine kinase inhibitors (Jones et al. 2004, 2005, 2006a). Therefore, the dominance of the EGFR pathway in the parental cells is replaced by the elevated use of the IGF-1R in the gefitinib resistant cells.

However, such growth factor pathway switching can result not only from changes occurring during the development of acquired resistance, but critically can also occur very rapidly and may modulate initial sensitivity to EGFR-blockade resulting in de novo or intrinsic resistance to anti-EGFR agents, such as gefitinib. Indeed, although classically, EGFR and IGF-1R pathways are normally regarded as separate entities, promoting growth through the use of overlapping downstream signal transduction molecules, abundant evidence is emerging which indicates that these receptors can affect each others signalling abilities, although the precise mechanisms involved in this crosstalk are not fully understood. For example, gefitinib can only partially block EGFR activity in the A549 lung cancer cells and this is rapidly accompanied by a dramatic increase in the activity but not expression of the IGF-1R (Jones et al. 2006a). Moreover, in these cells, the IGF-1R can transphosphorylate the EGFR, thus maintaining EGFR activity in the presence of gefitinib. Thus, in this manner, gefitinib limits its own efficacy by facilitating IGF-1R activity in these cells. Interestingly, we have also observed that in de novo gefitinib-resistant LoVo colorectal cancer cells, which are defective in their ability to produce mature IGF-1R and express mainly insulin receptor-isoform A (InsR-A), a close family member of the IGF-1R, insulin receptor activity is again increased in the presence of gefitinib together with elevated downstream activated Akt levels (Jones et al. 2006b). Furthermore, as seen with the IGF-1R in the A549 cells the InsR can also modulate and maintain EGFR phosphorylation in these cells (Jones et al. 2006b). Such rapid and dynamic interplay between the EGFR and the IGF-1R or InsR may play an important role in limiting the anti-tumour activity of gefitinib seen in partial and de novo resistance to the inhibitor shown by the A549 and LoVo cells respectively. In support, evidence is accumulating which indicates that an association exists between elevated IGF-1R expression/signalling and its downstream components, such as Akt and resistance to drugs, which inhibit erbB family signal transduction in various cancers. For example, IGF-1R via PI3-kinase/Akt activation has been shown to mediate resistance to the selective EGFR tyrosine kinase inhibitor AG1478 in glioblastoma cells (Chakravati et al. 2002) and also to the anti-EGF-R monoclonal antibody 225 in DiFi human colorectal cancer cell line (Liu et al. 2001).

Factors mediating such interplay between the EGFR and the IGF-1R require elucidation and studies in our laboratory have implicated c-Src. We have shown that this non-receptor tyrosine kinase is a key regulator in the interplay that exists between the EGFR and the IGF-1R in our MCF-7-derived tamoxifen-resistant breast cancer cells, where the IGF-1R is unidirectionally permissive for EGFR signalling (Knowlden et al. 2005). It was observed that IGF-II treatment of the tamoxifen-resistant cells promoted c-Src activation, which directly associated with EGFR and enhanced its phosphorylation at the tyrosine residue pY845, a c-Src-specific EGFR phosphorylation site (Biscardi et al. 1999), facilitating more efficient EGFR activation at pY1068 (Knowlden et al. 2005). Conversely, challenge with the c-Src inhibitor SU6656 decreased both basal and IGF-II-induced c-Src activity, and also reduces EGFR phosphorylation at both pY845 and pY1068 (Knowlden et al. 2005). Indeed, IGF-1R signalling has been shown to be permissive for EGF-primed events in other signalling systems which include the observation that IGF-I is essential for EGF-mediated cell cycle progression in normal breast epithelial cells (Stull et al. 2002). Furthermore, functional IGF-1R is required for EGF-induced mitogenesis and/or transformation in mouse embryo cells (Coppola et al. 1994). The IGF-1R can also affect EGFR signalling by regulating the production or availability of the ligands for EGFR activation. For example, the IGF-1R has an involvement in the metallo-protease-dependent release of the EGFR ligands amphiregulin or heparin-binding EGF (Roudabush et al. 2000) and furthermore, IGF-IR has been reported to activate the EGFR via regulating the production of TGF- in colon carcinoma cells (Wang et al. 2002) and both TGF- and amphiregulin in human keratinocytes (Vardy et al. 1995).

	Receptor interactions

Top Abstract Introduction Pathway switching between the... Receptor interactions Co-targeting the EGFR and... Clinical relevance Conclusion References

 
Adding another layer of intricacy to an already complicated system of growth factor receptor pathway switching is the fact that although it is well established that members of the type I receptor tyrosine kinase (RTK) erbB family (erbB/HER 1–4) readily form heterodimers with each other (Gullick 2001) and members of the type II RTK family, such as the IGF-1R and InsR also form hybrid receptors (Adams et al. 2000), it is now becoming apparent that receptors from these heterologous families can also form physical associations with each other. Moreover, such interactions between different families of receptors may be integral to the regulation of their signalling in normal and cancer tissue, as well as drug-induced receptor crosstalk. For example, in normal breast epithelial cells, IGFs stimulate proliferation by activating the ERK mitogenic pathway via the EGFR tyrosine kinase activity by means of a direct physical association between the EGFR and the IGF-1R (Ahmad et al. 2004). It is also established that the IGF-1R can unidirectionally activate HER-2 and this involves a physical association between the two receptors (Balana et al. 2001). Interestingly, IGF-1R signalling has been implicated in mediating resistance to the anti-HER-2 agent trastuzumab (Herceptin) (Lu et al. 2001) and it has been recently shown that the resulting crosstalk from IGF-1R/HER-2 heterodimerisation contributes to trastuzumab resistance in breast cancer cells (Nahta et al. 2005). Similarly, our gefitinib-resistant breast cancer cells which show a loss of sensitivity to trastuzumab compared with their parental cells, also demonstrate evidence of the existence of a physical interaction between the IGF-1R and HER-2, which furthermore, co-localise at the tumour cell membranes (Jones et al. 2005). Interestingly, preliminary studies in our laboratory indicate that in our gefitinib-resistant breast cancer cells, activated IGF-1R can also physically associate with HER-3 and HER-4 and in addition, the presence of a complex between the InsR and HER-2 has also been determined in the LoVo colorectal cancer cells which can be further promoted by gefitinib and the significance of these findings is presently being evaluated. However, these observations suggest that extremely diverse and complex interplay exists between many members of the type I and type II RTK families which aids in cancer cell plasticity, ultimately impacting upon the efficacy of anti-tumour agents.

	Co-targeting the EGFR and IGF-1R

Top Abstract Introduction Pathway switching between the... Receptor interactions Co-targeting the EGFR and... Clinical relevance Conclusion References

 
Understanding the mechanisms which underlie the pathway switching between the EGFR and IGF-1R, key players in the maintenance of the malignant phenotype, will aid in the elucidation of resistance to agents, such as gefitinib and potentially, the anti-IGF-1R drugs which are presently under development in the preclinical and clinical studies (Hofmann & Garcia-Echerverria 2005), which no doubt, will not be spared the phenomena of acquired or de novo resistance. Such knowledge is essential to rationally design drug combination regimes in order to improve drug efficacy and maximise anti-tumour effects and emerging preclinical data indicates that co-targeting the EGFR and the IGF-1R should be beneficial in enhancing the efficacy of gefitinib. Indeed, we have already shown that the acquisition of gefitinib resistance in our tamoxifen-resistant breast cancer cells can be delayed or even prevented by the combination of gefitinib plus an IGF-1R inhibitor, confirming that IGF-1R is a key compensatory cell survival mechanism acquired during gefitinib treatment to promote resistance (Nicholson et al. 2004). Other workers have demonstrated that the growth inhibitory effects of gefitinib, notably, its ability to induce apoptosis, can be enhanced by the co-inhibition of IGF-1R signalling in a range of breast cancer cell lines (Camirand et al. 2005). A bispecific antibody, known as Di-diabody that targets both the IGF-1R and EGFR has been developed and has been shown to possess in vivo anti-tumour effects in colorectal and pancreatic carcinoma xenografts (Lu et al. 2005). In addition, co-targeting the EGFR and the IGF-1R has also been effective in synergistically sensitising glioma cells to apoptosis (Steinbach et al. 2004) and recently, the blockade of IGF-1R signalling with the humanised anti-IGF-1R antibody h7C10 was shown to enhance the anti-tumour effects of vinorelbine and the anti-EGFR antibody 225 in human breast and lung cancer xenografts (Goetsch et al. 2005).

Critically, we have also demonstrated that in LoVo colorectal and A549 lung cancer cells which are de novo resistant and only partially responsive to gefitinib respectively, co-targeting the type II RTKs with EGFR in these cells, results in a small but significant additive effect on the inhibition of growth compared with single agent treatment (Jones et al. 2006a,b). Moreover, chronic exposure to the combined agents resulted in total cell loss and not only prevented the acquisition of resistance to gefitinib in the A549 cells but additionally, the development of resistance to an IGF-1R/InsR tyrosine kinase inhibitor was also prevented in both cell lines (Jones et al. 2006a,b). To date, signalling analysis in the LoVo cells has indicated that this increased efficacy of the combination drug regime results from the fact that once the resistance mechanism modulating EGFR activity has been blocked, which in these cells is InsR-A signalling, gefitinib effects are restored as determined by its ability to reduce EGFR phosphorylation which can impact further on growth (Jones et al. 2006b). Therefore, given that there appears to be a dynamic interplay between the EGFR and the IGF-1R/InsR with the latter receptors modulating EGFR activity, it is logical to hypothesise that cells which have acquired resistance to the IGF-1R/InsR inhibitor as a result of chronic exposure would readily switch to EGFR signalling, with the subsequent reinstatement of sensitivity to EGFR inhibition. Indeed, in complete contrast to the parental cells, the variant LoVo subline with acquired resistance to the IGF-1R/InsR inhibitor that emerged during our long-term treatment studies, demonstrates acute sensitivity to gefitinib which is accompanied by a substantial fall in EGFR phosphorylation (Jones et al. 2006b). The role of EGFR signalling in our A549 subline with acquired resistance to the IGF-1R/InsR inhibitor is presently being evaluated.

	Clinical relevance

Top Abstract Introduction Pathway switching between the... Receptor interactions Co-targeting the EGFR and... Clinical relevance Conclusion References

 
Clinical data have indicated that a high level of de novo resistance exists to EGFR tyrosine kinase inhibitors and even the duration of response (3–12 months) displayed by responders to gefitinib in various different cancer types (Ranson et al. 2002, Schiller 2002, Kelly & Averbuch 2004, Rothenberg et al. 2004) indicates the fairly rapid acquisition of resistance to the inhibitor. The identification of patients with intrinsic resistance to anti-EGFR therapy is essential to aid treatment selection and preclinically, many studies have implicated the IGF-1R as being one mechanism that can modulate responses to anti-EGFR agents. Interestingly, however, a recent study demonstrated that IGF-1R expression was not associated with intrinsic gefitinib resistance in patients with non-small cell cancer but the authors acknowledged that this biomarker should be evaluated further with regard to acquired resistance (Cappuzzo et al. 2006). However, the levels of the expression of IGF-1R alone may not be rate-limiting in determining gefitinib response or failure. In agreement, we have observed that in our tamoxifen-resistant MCF-7-derived cells, IGF-1R is central in the promotion of EGFR signalling, where these cells show lower expression levels but higher activity of the IGF-1R compared with their parental cells (Knowlden et al. 2005). Similarly, compared with the afore-mentioned tamoxifen-resistant cells, our subsequently derived dually tamoxifen/gefitinib-resistant breast cancer variant demonstrates an enhanced dependency on IGF-1R signalling and, in fact, shows a further reduction in IGF-1R expression but again, an elevation in activity (Jones et al. 2004). This inverse relationship between IGF-1R expression but elevation in receptor activity and increased dependency on IGF-1R signalling, suggests that it seems likely that the measurement of the activation status of the IGF-1R may prove fundamental in the assessment of this receptor as a biomarker for response to anti-EGFR therapy.

However, it is encouraging that on the basis that numerous preclinical studies showed that gefitinib is growth inhibitory to a range of human oestrogen receptor ER-positive and -negative breast cancer xenografts and cell lines (Ciardiello et al. 2000, Chan et al. 2002, Gilmore et al. 2002, Wakeling et al. 2002), including our MCF-7-derived EGFR-positive acquired tamoxifen-resistant breast cancer cells (Knowlden et al. 2003), subsequent phase II clinical trials assessing the efficacy of gefitinib monotherapy have shown that gefitinib demonstrated clinical benefit in patients with advanced breast cancer (Baselga et al. 2003) and also ER-positive patients with acquired tamoxifen resistance (Gee et al. 2004, Gutteridge et al. 2004). However, it is noteworthy that the latter study indicated that the responsive group in fact displayed ER positivity and only modest EGFR expression prior to and after 8 weeks gefitinib treatment. In contrast, the majority of the ER-negative/overexpressing EGFR patients were de novo resistant to gefitinib (Gee et al. 2004). Interestingly, this equates with our in vitro model system data for ER-positive acquired tamoxifen resistance, where we have shown that modestly increased EGFR signalling is growth contributory (Knowlden et al. 2003). The dynamic interaction that occurs between the EGFR and the IGF-1R should not be ignored when evaluating responses to anti-EGFR agents, such as gefitinib and we believe that signalling via the IGF-1R plays significant contribution in modulating the sensitivity and duration of response to these therapies. It is also possible that in EGFR-positive tumour cells, including breast cells that are insensitive or only partially responsive to gefitinib, existing IGF-1R activity may also play an important role in the maintenance of cell proliferation. This feasibly could encompass ER-negative/EGFR-positive disease, where gefitinib responses appear to be minimal and where we have shown that IGF-1R expression, activity and additionally downstream Akt signalling is present at significant levels in such intrinsically gefitinib-resistant clinical material (Gutteridge et al. 2004, Agrawal et al. 2005).

	Conclusion

Top Abstract Introduction Pathway switching between the... Receptor interactions Co-targeting the EGFR and... Clinical relevance Conclusion References

 
Cancer cells are highly adaptive and they can readily pathway switch in order to maintain growth or cell survival, a process paradoxically that in many instances is induced by the anti-cancer drugs themselves, thus limiting their activity and promoting resistance. Targeting of pathway switching improves the anti-tumour activity of existing anti-growth factor therapies, either improving cell kill or even creating responses in previously insensitive cells. It is hoped that the application of these general principle\kern-2pts into clinical practice will have great potential to improve responses in a wide variety of anti-cancer agents and through intelligent design of therapeutic strategy, significantly improve patient outlook.

	Acknowledgements

 
Thanks to the Tenovus Tissue Culture Unit, Immunocytochemistry Unit, Sarah Razzaq and Ian Lewis for technical assistance, Lynne Farrow for statistical analysis and the Tenovus Cancer Charity for additional support. Helen E Jones, Julia M W Gee, and Robert I Nicholson are in receipt of funding from AstraZeneca, the latter additionally being a member of an advisory board for AstraZeneca. The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work.

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