Primary Double-Strike Therapy for Cancers to Overcome EGFR Kinase Inhibitor Resistance: Proposal from the Bench

Abstract

Diverse molecular mechanisms that confer acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in lung cancers with sensitive EGFR mutations have been reported. However, it is not realistic to analyze for all these mechanisms at the time of resistance in clinical practice and establish adequate treatment targeting these numerous resistance mechanisms. Therefore, we believe that we should move our research focus from the exploration of “established” diverse resistance mechanisms to the elucidation of molecular mechanisms that enable cancer cells to remain alive at the early phase of the treatment. Here in this review, we summarize up-to-date molecular mechanisms that maintain residual tumor cells against EGFR TKI monotherapy in lung cancers with EGFR mutations. We classified these mechanisms into three categories. The first is a pre-existing minor subpopulation with a resistance mechanism such as a pretreatment T790M mutation that can be detected by highly sensitivity methods. The second is the reversible drug-tolerant state that is often observed in cell line models and accounts for the lack of complete response and continued survival of cells exposed to EGFR TKIs in patients. And the last is the role of the microenvironment, including survival signaling from fibroblasts or dying cancer cells and the role of poor vascularization. Primary double-strike cancer therapy, or even initial multiple-strike therapy, to cancer cells that cotarget EGFR and survival mechanism(s) simultaneously would be a promising strategy to improve the outcomes of patients with EGFR mutations.

Semaphorin 7A promotes EGFR-TKI resistance in EGFR mutant lung adenocarcinoma cells

“…Intrinsic and acquired forms of resistance to EGFR-TKI represent critical problems to be solved. In addition, drug tolerant states have also been reported, and some of these obstacles to treatment are directly involved in driver mutation signals (14).…”

Evolution of Tyrosine Kinase Resistance in Egfr Mutated Non-Small Cell Lung Cancer

“…Другое направление по улучшению результатов ле-чения больных с активирующими мутациями связано с предотвращением возникновения резистентности за счет максимального воздействия на наивную с точки зрения противоопухолевого лечения опухоль -«double-hit» [61]. Среди направлений можно выделить различные варианты дозирования уже зарегистриро-ванных препаратов, комбинации с цитостатиками, антиангиогенными и непротивоопухолевыми препа-ратами, включая средства нетрадиционной китайской медицины [40][41][42][43][44][45][46][47].…”

The integration of genomics testing and functional proteomics in the era of personalized medicine

“…A more comprehensive molecular view of cancer is necessary to enable the precise selection of combinatorial targeted therapies for tumor elimination with minimal side effects [32]. Therapeutic resistance to RTK inhibitors is classified into innate resistance, owing to the insufficient activation of the targeted RTK, the aberrant activation of other RTKs that bypass the targeted therapy, or canonical WNT ligand-dependent β-catenin signaling activation, and acquired resistance, owing to secondary mutations in the targeted RTK [23,[33][34][35][36]. For example, lowlevel expression of FGFRs or co-overexpression of EGFR, ERBB2, ERBB3, or MET with FGFRs in cancer cells with FGFR gene amplification leads to FGFR inhibitor resistance.…”