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Gurule et al. Cancer Drug Resist 2018;1:118-25 I http://dx.doi.org/10.20517/cdr.2018.12 Page 119

ONCOGENIC RECEPTOR TYROSINE KINASES AS TARGETS FOR PRECISION MEDICINE
Malignancies of epithelial tissues account for 80 to 90 percent of all cancer cases, making carcinomas the
[1]
most common histological type of cancer . Activating mutations in receptor tyrosine kinases (RTKs) and
their associated downstream signal pathways function as oncogene drivers in many solid tumor types. Lung
adenocarcinomas (LUADs) serve as an example of a carcinoma arising from distinct pulmonary epithelial
cells that harbor many diverse oncogenic RTKs including EGFR, ALK, MET, and ROS1 . Moreover, specific
[2]
tyrosine kinase inhibitors (TKIs) are now routinely deployed as first-line therapies in patients with lung
tumors presenting with these oncogenic RTKs. Examples of these TKIs include gefitinib or osimertinib for
EGFR, and crizotinib or ceritinib for ALK, ROS1 and MET. Cetuximab, a monoclonal antibody against EGFR
is also used to treat patients with head and neck squamous carcinoma (HNSCC), which often overexpress
[3]
EGFR . Thus, these oncogene targeted agents have proven efficacious for inducing tumor regression as first-
line therapies, although complete responses are rare and emergence of acquired resistance is universal .
[4]
Although TKIs are less toxic than traditional cytotoxic drugs, their use is still associated with various adverse
effects including skin toxicity, hematological deficiencies, nausea, vomiting, diarrhea, and headaches being the
most common side effects. Skin toxicities are very frequent, occurring in 49%-95% of patients treated with
[5-7]
EGFR inhibitors, and 16% of patients treated with ALK/c-MET inhibitors . More acute and often fatal side
effects such as liver toxicity and forms of interstitial lung disease (ILD) occur at a lower frequency in cancer
patients treated with the TKIs gefitinib, erlotinib, and crizotinib . ILDs such as pneumonitis and pulmonary
[8,9]
fibrosis occur at frequencies of < 1% and 1.6% respectively with EGFR inhibitors and ALK inhibitors [5,10] .

The role of EGFR in regulating cellular proliferation, survival, and differentiation during development, tissue
homeostasis, and carcinogenesis is well established. EGFR is expressed in a variety of normal epithelial
tissues including skin . Within the epidermis, EGFR is most prominently expressed in proliferating basal
[11]
and suprabasal keratinocytes. In keratinocytes, EGFR signaling sustains proliferation and migration and
delays apoptosis in suprabasal keratinocytes that are no longer attached to matrix [12-14] . In addition to normal
keratinocyte dependent skin homeostasis, EGFR signaling functions in the protective response triggered by
epithelial cells during wound healing or during defense against microorganisms that cause skin infections.
EGFR is also highly expressed in alveolar type II epithelial cells in the lung [15,16] . The MET tyrosine kinase
receptor and its ligand HGF have well characterized functions in tissue remodeling via regulating cellular
processes such as proliferation, apoptosis, morphogenic differentiation, motility, invasion and angiogenesis.
MET is expressed on the surface of epithelial cells in the liver, pancreas, prostate, kidney, and lung and is
[17]
essential for both embryonic liver development and liver regeneration after injury [18-20] .

RECEPTOR TKIS DE-REPRESS INNATE IMMUNE RESPONSES IN TUMOR CELLS AND NORMAL
EPITHELIAL CELLS
As previously mentioned, acneiform rash is an established side effect of both small molecule and antibody-based
inhibitors of EGFR , typically presents within the first two weeks of administration of EGFR inhibitor and is
[21]
a positive predictor of response to therapy. Not only is there a positive correlation between rash and therapeutic
response of the tumor, but progression free survival and overall survival are also positively correlated with
presence of these skin toxicities [22-25] . There are three main contributors to EGFR inhibitor induced skin toxicity;
damage to the epithelial barrier, loss of antimicrobial mechanisms, and extensive release of inflammatory
chemokines and cytokines. For the purpose of this article, we will focus on TKI mediated chemokine and cytokine
release. The mechanisms contributing to damage to the integrity of the epithelial barrier and antimicrobial
defense loss has been previously reviewed . The EGFR inhibitor-induced inflammation is characterized by
[26]
robust release of chemokines and cytokines that recruit and activate distinct immune cell populations including
dendritic cells, macrophages, granulocytes, mast cells and T cells [12,13,27] . Mechanistically, Pastore and colleagues
have demonstrated that this inflammatory phenotype is largely driven by a type I interferon (IFN) response