Resistance to epidermal growth factor receptor inhibition in non-small cell lung cancer

Abstract

Aberrant activation of the epidermal growth factor receptor (EGFR) is a driving force for cancer growth in a subgroup of non-small cell lung cancer patients. These patients can be identified by the presence of activating EGFR mutations. Currently three generations of EGFR-tyrosine kinase inhibitors (TKIs) have been approved by the Food and Drug Administration and European Medicine Agency. This paper reviews the structure of EGFR and the downstream signaling pathways of EGFR and describes the mechanisms of intrinsic and acquired resistance against EGFR-TKIs. These mechanisms include secondary or tertiary mutations in EGFR, the activation of bypassing signaling pathways or a histological transformation to small cell lung cancer. Moreover, drug efflux transporters will affect the cellular accumulation of EGFR-TKIs and penetration of the first generation of EGFR-TKI into the brain. Lysosomal sequestration of some EGFR-TKIs may also prevent the drugs to reach their target. In conclusion, resistance to EGFR-TKIs is multifactorial, including primary and acquired mutations in the EGFR gene, activation of bypassing pathways and limited uptake of drugs in the cells or target tissues. More pharmacological studies are needed in order to develop new specific compounds targeted to overcome new resistance mechanisms in order to enable a personalized treatment approach.

The Role of c-Met as a Biomarker and Player in Innate and Acquired Resistance in Non-Small-Cell Lung Cancer: Two New Mutations Warrant Further Studies

“…In this case, the activation of the c-Met receptor represents a crucial factor, which warrants further study to determine the phosphorylation status of c-Met. Thus, in cases where a higher c-Met expression is coupled to a higher activation of c-Met, this opens the door to combine EGFR and c-Met inhibitors, including the screening for c-Met activation together with EGFR mutations, as previously postulated [53,54].…”

Is there a role for dacomitinib, a second-generation irreversible inhibitor of the epidermal-growth factor receptor tyrosine kinase, in advanced non-small cell lung cancer?

“…Despite the initial encouraging clinical response, eventually, almost all patients developed resistance to firstgeneration inhibitors over time. This resistance was mainly caused by a point mutation in the kinase domain of EGFR, in particular mutation T790 M, which increased the ATP affinity for its binding site [11]. It should be noted that the T790 M mutation has been detected, in a small percentage of cases, as primary mutation in EGFR-TKI naïve patients [12].…”

“…It should be noted that the T790 M mutation has been detected, in a small percentage of cases, as primary mutation in EGFR-TKI naïve patients [12]. Additionally, D761Y, T854A, and L747 S are rare EGFR mutations that confer acquired resistance to first-generation TKIs [11]. Acquired resistance can be also caused by the activation of bypassing pathways, such as amplification of c-Met, overexpression of receptors FGFR1 and FGFR2 or of their ligands FGF2 and FGF9, loss of PTEN and over-expression of the Yes-associated protein (YAP) [11].…”

“…Additionally, D761Y, T854A, and L747 S are rare EGFR mutations that confer acquired resistance to first-generation TKIs [11]. Acquired resistance can be also caused by the activation of bypassing pathways, such as amplification of c-Met, overexpression of receptors FGFR1 and FGFR2 or of their ligands FGF2 and FGF9, loss of PTEN and over-expression of the Yes-associated protein (YAP) [11]. Consequently, a second generation of TKIs was designed, including afatinib (Giotrif®, Boehringer Ingelheim; Ingelheim, Germany) and dacomitinib (VIZIMPRO®, Pfizer Inc., New York, NY, USA), the latter being the main subject of this review.…”

Activated Protein Kinase C (PKC) Is Persistently Trafficked with Epidermal Growth Factor (EGF) Receptor

“…Although EGFR is the target of many anti-cancer drugs, resistance to these drugs inevitably develops (review [1]). Drug resistance is often acquired through a mutation in the receptor itself or through changes that alter receptor processing so as to enhance signaling from the receptor (review [2]). As more than one member of this receptor family can coexist in a cell, together they assemble a scaffold on which a vast variety of other molecules can be assembled.…”