Kinase-driven pathways of EGFR in lung carcinomas: perspectives on targeting therapy

Abstract

Despite remarkable advances in oncology medicine, the prognosis of lung cancer patients has not greatly improved over the past few decades. To overcome the current limit, new classes of agents that specifically target particular cascades have been developed. Gefitinib and erlotinib, which are tyrosine kinase inhibitors specific for the epidermal growth factor receptor (EGFR), have provided hope for better survival. The relationship between the sensitivity to gefitinib and the tumors' EGFR mutations have allowed the selective and accelerated use of these therapies. However, their efficacy is still limited, predominantly due to side effects and drug resistance. Further development of rational clinical strategies will require greater clarification of the key signaling factors downstream of EGFR which are potential targets for cancer therapies. In this review, we describe the various observed abnormalities in EGFR, the mechanisms of activation of several critical signaling cascades in lung cancer. Summarizing the data gleaned from preclinical, and clinicopathological aspects, we discuss the molecular mechanisms that may underlie a possible successful response to the blockade of EGFR and/or its downstream signaling.

Combined inhibition of insulin-like growth factor-1 receptor enhances the effects of gefitinib in a human non-small cell lung cancer resistant cell line

“…The mechanism of the IGF-1R pathway involvement in cellular resistance to gefitinib remains unclear. Further development of rational clinical strategies require greater clarification of the key signaling factors which are potential targets for cancer therapies (29). The data presented here support further research into NSCLC therapeutic strategies combining gefitinib with anti-IGF-1R agents.…”

Targeting the PI3K/Akt/mTOR pathway in non‐small cell lung cancer (NSCLC)

“…The importance of the PI3K/Akt/mTOR pathway also extends to its role in tumors with other known activating mutations, such as EGFR and KRAS . Studies suggest that in patients with an EGFR mutation, the Akt/mTOR pathway is constitutively activated in 67% of cases . Additionally, another study revealed 18% of specimens showed positive staining for p‐EGFR, p‐Akt and p‐mTOR, indicating the importance of this signaling cascade .…”

Molecularly Targeted Therapy: Great Progress or Evil Cycle

“…During the history of MTT, the first application of imatinib in CML and association between EGFR mutations and gefitinib sensitivity in NSCLC were breakthrough discoveries. These genetic lesions are activating aberrations within or involving the target kinase genes and have prompted efforts to stratify patients based on the specific genomic profile of the cancer [2]. The pitfall of not establishing such an identification system was seen in the trials of gefitinib, which involved a large number of NSCLCs with EGFR over-expression that subsequently demonstrated only a small fraction of responsive population.…”

“…In addition to the causative mutation of the responsible gene, the intrinsic heterogeneity of cancers that harbor multiple gene aberrations could cause resistance. Moreover, in clinical samples, many studies generally affirmed the crosstalk between the various levels of different signal pathways [2]. Despite the wealth of information, a global understanding of the mechanism of resistance is sometimes hard, and thus, the combating resistance is still the important issue and the strategies have been conducted.…”

“…This strategy derived from the notion that cancer cells usually become more dependent on and addicted to the activity of a specific molecule which in most cases, is an oncogene product. Along with the prevalence of this concept "oncogene addiction", this novel and specific therapy called "tailored targeted therapy" came true for each patient [1,2]. The rationale of targeting the molecule selectively overexpressed or activated in cancer cells is that cytotoxicity will be selective/specific for cancer cells, minimizing potential adverse events (AEs).…”