The Presence of Autonomous and Non-Autonomous Replication in Cancer and their Connection through Inflammation


The Presence of Autonomous and Non-Autonomous Replication in Cancer and their Connection through Inflammation

Targeted therapy with small molecule such as TKI (tyrosine kinase inhibitor) against EGFR has achieved high response rate and significant clinical benefits in selected group of lung cancer patients in the past decade. One reliable criterion for patient selection is the presence of certain mutations in the EGFR gene such as mutations in exon-19, 20 or 21 in lung cancer patients. In these patients, it is often observed that TKI therapy could be so effective even against late stage tumors, that patients experience rapid relieve of clinical symptoms and stable control of disease progression for a extended period of time, often lasting for months even years. It has been assumed that the mechanism behind such significant disease control is the total inhibition of the kinase function of the targeted TK molecule by the small inhibitors given daily, so that no tumor replication can take place and inhibited tumor cells die of apoptosis. This mechanism would assume that all tumor cells in a tumor contain the targeted mutation, otherwise how are non-targeted tumor cells controlled? Yet the actual measurement of mutation frequency in almost all cases show a much lower rate of mutated  cells, often less than 40%. Then, a question arises: why don’t the remaining, non-mutated cells replicate in the presence of the drug? This question has not been satisfactorily addressed despite of its obvious existence in many TKI treated cases of cancer. Here we report our observations and treatment process in one lung cancer patient. The patient had 28% EGFR gene mutation and experienced stable disease control over two years of continuous TKI therapy and a rapid rebound of tumor relapse associated with return of clinical symptoms during a brief drug withdraw of 13 days followed by return of tumor and symptom control upon resumption of TKI therapy. These observations support the explanation that there are two types of tumor cell replication in an established tumor, one self-driven through the function of specific mutation that makes the cell cancerous (EGFR in this case) and the other non-autonomous and dependent on the active replication of the former through induction of inflammation. Control of the entire tumor progression depends on the relationship between these two populations of tumor cells.

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