Sensitivity of EGFR Mutants to TKIs The Oncogenic Shock Model

EGFR mutants are able to promote in vitro cellular transformation when expressed ectopically (62). The growth of these mutant EGFR-transformed cells can be potently inhibited with gefitinib and erlotinib. By a similar token, mice harboring human EGFR mutant transgenes, whose expression is under the control of doxycycline-dependent transcription, rapidly develop lung tumors with features reminiscent of human brochioalveolar adenocarcinoma, when given oral doses of doxycycline (63,64). When doxycycline administration is discontinued, the lung tumors regress, a phenomenon that can be mimicked with multiple EGFR antagonists, including TKIs and monoclonal antibodies. Thus, NSCLC cells expressing mutant EGFRs may rely solely on the oncogenic activity of the receptors for growth and viability.

At this point, it may be prudent to introduce the theory of "oncogene-addiction" (65). This model postulates that cancer cells, upon transformation by a single hyperactivated oncogene, become heavily reliant or dependent on its activity for growth and survival. Essentially, the cancer cell is in a state of equilibrium in which pro-growth and anti-apoptotic signals emanating from the transforming oncogene—EGFR, for example— counterbalance pro-apoptotic signals that are invariably triggered when a cell becomes transformed in efforts to facilitate a self-destruct mechanism. When the oncogenic stimulus is removed—for instance by pharmacologic intervention—the counterbalance is disturbed and the equilibrium shifts. Pro-apoptotic signals eventually predominate, resulting in programmed cell death of the cancer cells. This has now become entrenched as a central dogma in the rationale for target-based drug discovery efforts and has implications for the design of kinase inhibitors to target the activities of oncogenic kinases, such as B-Raf, EGFR, and other receptor tyrosine kinases. The theory also helps to explain the efficacy of proven target-based anti-cancer drugs such as imatinib for BCR-Abl and gefitinib or erlotinib for EGFR.

Another interesting point to note is that NSCLC cell lines harboring EGFR mutations display gene amplifications of the mutant alleles which suggests that there may be a great selective advantage for elevated EGFR activation in these cancer cells. This amplification of the locus seems somewhat counterintuitive in the context of hypersensitivity of mutant versus wild-type EGFR to EGFR TKIs, because one may predict that a higher concentration of drug would be required to inhibit the higher number of total receptors expressed. However, this would suggest that limited drug bioavailability is not a significant issue.

A variation of the oncogene addiction model, referred to as "oncogenic shock" (66,67) may explain the paradox of hypersensitivity to EGFR TKIs despite amplification of the gene (Fig. 3). This model suggests that transforming oncogenes, such as EGFR mutants, concomitantly activate both pro-survival and pro-death signaling pathways. Upon removal of the oncogenic stimulus, there are differences in the temporal attenuation of

Fig. 3. The oncogenic shock model. Tumor cells exhibit an equilibrium between pro-survival and pro-apoptotic signals, such that pro-survival predominates. Upon disruption of the oncogenic driving-force, the pro-survival signals dissipate at a more rapid rate than the pro-apoptotic signals, such that there is a period during which pro-apoptotis predominates. Thus, tumor cells undergo tumor cell death.

Fig. 3. The oncogenic shock model. Tumor cells exhibit an equilibrium between pro-survival and pro-apoptotic signals, such that pro-survival predominates. Upon disruption of the oncogenic driving-force, the pro-survival signals dissipate at a more rapid rate than the pro-apoptotic signals, such that there is a period during which pro-apoptotis predominates. Thus, tumor cells undergo tumor cell death.

the counterbalancing growth and death signals. In simple terms, the pro-survival signals dissipate very rapidly upon disruption of the oncogenic stimulus, but pro-death signals decay at a slower rate, such that they eventually outweigh the survival signals, resulting in apoptotic cell death. Thus, in NSCLC cells harboring amplified EGFR mutants, gefitinib- or erlotinib-induced cell death may be due to a large pro-death output emanating from activated EGFR.

This mechanism could certainly explain why cells over-expressing the mutants are exquisitely sensitive to EGFR TKIs. Untransformed or normal cells are not sensitive to these drugs because they do not exhibit this fine balance between pro-survival and pro-death exhibited by tumor cells that are heavily dependent on a single oncogenic stimulus. Thus, target-based anti-cancer agents such as imatinib, gefitinib, and erlotinib display relatively low toxicity indices.

The oncogenic shock model also has implications for combined chemotherapeutic regimens with targeted therapies (such as erlotinib) and conventional DNA damaging agents (such as gemcitibine). For instance, chemotherapeutic agents that trigger a DNA damage-induced checkpoint, resulting in mild growth arrest or apoptosis, may attenuate the effects of target-based therapies that attack the oncogenic driving force directly, which trigger a delayed but sustained pro-death response. Indeed, in clinical practice, the combination of gefitinib or erlotinib with traditional chemotherapeutic agents has not yielded a statistically significant increase in survival benefit (68).

Finally, the oncogenic shock model suggests that in future drug-discovery endeavors, time-courses of drug action as well as traditional dose response analyses may need to be analyzed. In the case of EGFR, it is clear that anti-EGFR monoclonal antibodies exhibit a different toxicity profile than TKIs, which may be related to the rate at which EGFR signaling is "shut-off' with the two modalities. Thus, drugs that are faster acting in terms of attenuation of pro-survival signals may prove to be more efficacious in treating certain cancers.

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