Novel potential strategies to overcome resistance to anti-EGFR targeted therapy

Activating epidermal growth factor receptor (EGFR) mutations account for about 16% of non-small cell lung cancer (NSCLC). Over the past decade, three generations of anti-EGFR tyrosine kinase inhibitors (TKIs), have been approved at the clinical level for the treatment of advanced EGFR-positive patients. However, the therapeutic benefit is short-lived for the emergence of sub-clones that are resistant to targeted therapy. Recent preclinical and translational studies have proposed novel strategies to overcome drug resistance. Interestingly, the use of a structure-function method to classify EGFR mutations better select patients who can benefit of a specific drug, than the use of a classic exon-based categorization. Moreover, this approach recognizes a new class of EGFR alterations, the PACC mutations, that can be also acquired and that are particularly sensitive to second-generation TKI, also when used at low dosage. Another alternative strategy is the use of combination therapy that exploits both first and third generation inhibitors. Indeed, while the EGFR C797S mutation cause resistance to third generation TKIs, it retains sensitivity to first generation molecules. For EGFR Ex 19 del/T790M/C797S triple mutants this combination regimen is also effective, but only if the T790M and C797S acquired mutations are in trans on EGFR alleles. Finally, I discuss the development of anti-EGFR allosteric inhibitors, that are able to bind EGFR on a different pocket respect to ATP-mimetic inhibitors. This different class of compounds are effective in both EGFR TKI sensitive and resistant cells, including those positive for EGFR T790M and C797S mutation. However, they are effective only on EGFR monomer, a condition facilitated by the co-administration of TKIs. Overall, these studies provide a general overview of different novel therapeutic strategies to fight drug resistance to anti-EGFR targeted therapy and that can potentially ameliorate the outcomes of patients with NSCLC.