Abstract
Since the discovery of tyrosine kinase inhibitors in treatment of lung cancer harboring such actionable targets, many lives have been prolonged. To the same extent, same group of patients have failed to benefit from this category of drugs, in long run, either initially or during the course of treatments, simply due to either known or unknown mechanism of resistance which occurs very often in the first few months after initiation of therapy. The resistance is 100 percent expected, and no patient is reported to be a waiver of such pattern. With best practices of oncology, the average duration of response is expected to be below 12 months [1]. About half of the resistance is caused by mutation at T790M in EGFR target, which can be revealed by liquid biopsy [1] [2]. The most recent studies have revealed the significant role of epigenome in controlling this complicated resistance pattern. We have learned that Histone deacetylation, as opposed to promoter methylation, may contribute to the epigenetic silencing and to EGFR TKI resistance in NSCLC [3] [4]. Here we present a case study with a model of combinational therapy that targets the EGFR molecule, (by small molecule inhibitor, Afatanib) with simultaneous epigenetic modification of the target, (by application of multitargeted epigenetic therapy (MTET) with significantly improved clinical results. We propose further trials are needed to support such hypothesis, which if proved, could significantly shift the current practices in management of this set of cases in lung adenocarcinomas.
Highlights
IntroductionDue to connection of Hepatocyte growth factors to Met pathway, it is speculated that in about 61 percent of cases, studies in Japan, HGF overexpression was responsible in promoting drug resistance [6]
50% of the acquired resistance developed to erlotinib or gefitinib is linked to T790M mutation and the proportion could be underestimated as more accurate prevalence of 68% was achieved using LNA-PCR/sequencing assay [5]
In case number 1, a mutated EGFR tumor responds to epigenetic therapy in combination with afatinib
Summary
Due to connection of Hepatocyte growth factors to Met pathway, it is speculated that in about 61 percent of cases, studies in Japan, HGF overexpression was responsible in promoting drug resistance [6]. This mechanism is INDEPENDENT of TKI pathways. That said application of several dual targeted therapies to target Pi3k/Akt, has not resulted in improved survival in these patients [7]. Her 2 alteration, is seen in about 2 percent of cases. Epidermo mesenchymal Transition (EMT) phenotypic transformation has been proven in at least 5 percent of cases with EGFR resistance as main mechanism. [8] [9] [10]
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