DOI:  https://www.doi.org/10.31917/1902106

Discovery of TKI-sensitizing EGFR mutations (EGFR-M+) in non-small cell lung
cancer (NSCLC) is often regarded as the most spectacular event in clinical oncology
during last decades. However, treatment with drugs targeting EGFR (TKIs) almost
never results in complete tumor eradication and inevitably results in the regrowth of
tumor. Inevitably after dramatic primary response to TKI in EGFR mutated NSCLC all patients develop disease progression. Development of resistance to targeted therapies is a major contributor to mortality
in patients with oncogene addicted NSCLC. Since EGFR mutation is an early event in carcinogenesis the absolute majority
of tumor cells harbor activating mutation prior to treatment with TKI. This relative homogeneity underlies high frequency
and depth of primary responses to TKI. Still EGFR driven tumors have genetic instability that influences mutational burden
and sub-clonality though in a lower level than in tumors without activating mutations. Several mechanisms are shown to
drive acquired resistance. Among them EGFR bypass (including MET, HER2, BRAF, etc.) and EGFR ATP pocket alterations
(i.e. T790M, C797S, etc.) as far as phenotypic transformation to small cell lung cancer (EMT). Still the properties and
mechanisms of transitional state from sensitive to resistant status are studied insufficiently. Two actual explanations for
primary insensitivity are described in the literature. First, there are preexisting low-frequency clones that harbor resistance
mechanisms identified at the time of clinical progression. Second, some genetically indistinguishable cells during first
weeks of treatment acquire phenotypical properties (drug tolerant status) that allow them to survive first TKI pressure,
divide and proliferate, and therefore develop resistance mechanisms. While the acquired resistance mechanisms are studied
heavily enough, there are only few identified molecules that probably participate in phenotypical transformation to «drug
tolerant status». Among them Wnt/tankyrase/β – catenin pathway, casein kinase 1a, IGF-1R, STAT3 are shown to make EGFR
mutated cells insensitive to TKI. Identification of the mechanisms underlying incomplete block of tumor cells proliferation
during first period of treatment with either TKI in oncogene addicted NSCLC will help to change primary treatment and
therefore to cure these patients.