![]() The emergence of the T790M mutation inspired efforts to develop agents that act in a mutant-selective manner to overcome drug resistance. Second-generation irreversible inhibitors such as afatinib can inhibit the T790M variant, but are also very potent inhibitors of the WT receptor, leading to a very narrow therapeutic index and toxicity 10, 11. The T790M mutation occurs at the so-called gatekeeper residue and results in enhanced affinity for ATP thereby greatly decreasing the potency of reversible ATP-competitive inhibitors 9. While most patients initially respond to treatment with reversible inhibitors, in many cases cancers become resistant through acquisition of the secondary T790M mutation. ![]() The first-generation reversible, ATP-competitive, small molecule tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib selectively inhibit the L858R variant by exploiting the decreased ATP affinity of this mutant EGFR 7, 8. The most common point mutation driver of NSCLC is EGFR(L858R), which activates the kinase while increasing K m,ATP 5, 6. In that population, activating mutations in the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, are a major cause of non-small cell lung cancer (NSCLC) 2– 4. While smoking is often cited as the major environmental risk for lung cancer, the incidence of lung cancer in never-smoking individuals has been on the rise. Importantly, lung cancer is the leading cause of cancer-related death worldwide for both men and women 1. These structural and mechanistic insights will aid in the identification and development of additional inhibitor combinations with potential clinical value.īased on the latest global statistics, lung cancer is the most common cancer in males and has the second highest incidence cancer in females after breast cancer. ![]() Mutation of F723 in the P-loop reduces cooperative binding and synergy, supporting a mechanism in which F723-mediated contacts between the P-loop and the allosteric inhibitor are critical for synergy. Structural analysis of these complexes reveals conformational changes occur mainly in the phosphate-binding loop (P-loop). We identify a subset of irreversible EGFR inhibitors that display positive binding cooperativity and synergy with the allosteric inhibitor JBJ-04-125-02 in several EGFR variants. Here, we examine combinations of ATP-competitive and allosteric inhibitors to better understand the molecular basis for synergy. Allosteric EGFR inhibitors offer promise as the next generation of therapeutics, as they are unaffected by common ATP-site resistance mutations and synergize with the drug osimertinib. Lung cancer is frequently caused by activating mutations in the epidermal growth factor receptor (EGFR).
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