On October 22, 2021 Purple Biotech (NASDAQ/TASE: PPBT), a clinical-stage company developing first-in-class, effective and durable therapies by overcoming tumor immune evasion and drug resistance, reported a publication in Nature Cancer that provides new insight into the underlying mechanism of the therapeutic resistance of cancer cells and the significant role of insulin receptor substrate 1 (IRS1) pathway on epithelial growth factor receptor (EFGR) inhibition therapy. NT219, currently being evaluated in a Phase 1/2 clinical trial, is a novel small molecule inhibiting simultaneously IRS1/2 and STAT3 (Press release, Purple Biotech, OCT 22, 2021, View Source [SID1234591780]).
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The article is titled, "IRS1 phosphorylation underlies the non-stochastic probability of cancer cells to persist during EGFR inhibition therapy," and is available online at: View Source The lead author of the publication is Ravid Straussman, M.D., Ph.D., Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
The article demonstrated mechanistic evidence of cancer cells’ inherited therapeutic resistance, termed chance to persist (CTP). It was shown in preclinical models, that the CTP EGFR inhibition is modulated by serine/threonine phosphorylation of the IRS1. Specifically, it has been shown that higher phosphorylation of IRS1 multiple serine/threonine sites, which blocks IRS1 activity, results in increased susceptibility to EGFR inhibitors. A combination of NT219, which triggers serine phosphorylation and subsequent degradation of IRS1 and EGFR inhibitors, resulted in a synergistic effect, leading to tumor regression and delayed recurrence upon treatment withdrawal.
"These results provide new insight into cellular persistence regulation and further advance the understanding of IRS1 inhibition in the cancer phenotype, as well as highlight the potential of NT219 to ameliorate tumor cell resistance to apoptosis," said Hadas Reuveni, Ph.D., VP Research and Development of Purple Biotech. "The results strengthen our previously published data on synergistic effects with certain anti-cancer agents, and further support our clinical development strategy of combining NT219 with anti-EGFR inhibitors."