Primary or De Novo Resistance to Egfr Tkis

The genetic basis for primary resistance to EGFR TKIs has been partly explained by clinical genotyping studies of NSCLC patients who are refractory to treatment. In one particular study of 38 patients who were deemed to be refractory to either gefitinib or erlotinib, 9 patients were found to harbor mutations in the K-Ras locus (70). K-Ras is mutated in approximately 30% of all NSCLC cases, and K-Ras mutation-positive tumors are associated with very poor prognoses, with such patients being highly refractory to conventional chemotherapeutic agents (71). Thus, many believe that K-Ras mutational status can be used as a clinical predictor of response to EGFR TKIs, although the present data sets do not achieve statistical significance. Oncogenic K-Ras exhibits many of the same signaling properties as EGFR, including the ability to drive growth and survival via the ERK and Akt pathways, respectively.

In tumors expressing mutant EGFR proteins, since K-Ras activation lies downstream of receptor activation, it may partially mediate EGFR-dependent neoplasia. It has been observed that mutations in EGFR and K-Ras are invariably mutually exclusive and never coexist. This is thought to be due to functional redundancy but instead may be due to a phenomenon known as a oncogene-induced senescence, in which the oncogenic stimulus, rather than driving cellular growth, induces exit from the cell cycle into the G0 phase, a process thought to be due to activation of the p16/Ink4A/ARF tumor suppressor locus (72).

Thus, mutational activation of EGFR and K-Ras within the same tumor cell may result in senescence when p16 or ARF activities have not been lost. Alternatively, EGFR and K-Ras mutations within the same tumor cell may trigger a strong apoptotic response that cannot be counteracted by the oncogenic stimulus. These scenarios are consistent with the oncogenic shock model, in that constitutively active variants of EGFR and Ras drive pro-death signaling pathways that may function in an additive manner, such that the coexistence of the two in a tumor may result in a selective disadvantage.

The molecular and cellular basis for primary resistance to EGFR TKIs in patients with K-Ras mutations is unclear. It has been suggested that K-Ras driven activation of the PI3 K-AKT-mTOR signaling pathway may be critical in establishing an EGFR-independent cellular survival framework. Thus, even though gefitinib and erlotinib may inhibit the kinase activity ofEGFR in cells harboring oncogenic K-Ras, the drugs cannot elicit a pro-death response because K-Ras is driving cell survival. An alternative and more complex hypothesis, however, may be the following.

As outlined above, it has been suggested that cells that have undergone EMT display an inherent or de novo resistance to gefitinib and erlotinib (61). It has been known for some time that oncogenic K-Ras has the potent ability to drive EMT in cells (73). Thus, it is possible that by inducing the transdifferentiation of epithelial cells to a mesenchy-mal state, oncogenic K-Ras facilitates the primary resistance to EGFR TKIs seen in the clinic. The vast majority of NSCLC patients who display primary resistance do not harbor K-Ras mutant alleles. The tumors from these patients may either exhibit alternative EGFR or K-Ras-independent survival signaling, or they may have undergone EMT independently of K-Ras activity, which are possibilities that remain to be validated.

A small subset of NSCLC patients that are refractory to treatment with EGFR TKIs, paradoxically harbor activating EGFR mutations (45). It has been shown that in mouse models of tumorigenesis, such as those driven by oncogenic Myc or K-Ras, most tumors regress upon removal of the oncogenic stimulus, which is consistent with the oncogene-addiction model. However, a small subset of tumors fails to regress if the initial oncogene remains active for sustained periods. This is thought to be due to the acquisition of secondary genetic lesions, which result in the oncogenic activation of other genes or the loss of tumor suppressor function. This may explain why some EGFR-mutation positive NSCLC cells display primary resistance to EGFR TKIs. For instance, it is possible that loss of expression of the PTEN tumor suppressor, via gene dysregulation or epigenetic mechanisms such as promoter hypermethylation (74) could lead to hyperactivation of PI3K signaling, because PTEN is a negative modulator of PI3K outputs (75). PTEN loss in the context of EGFR mutations can lead to EGFR-independent PI3 K signaling, resulting in a lack of response to drugs such as gefitinib and erlotinib.

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