2 research outputs found
Novel therapeutic strategies for patients with NSCLC that do not respond to treatment with EGFR inhibitors
Introduction: Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs)
yields tumour responses in non-small cell lung cancer (NSCLC) patients harbouring activating EGFR
mutations. However, even in long-lasting responses, resistance to EGFR TKIs invariably occurs.
Areas covered: This review examines resistance mechanisms to EGFR TKI treatment, which mainly arise
from secondary EGFR mutations. Other resistance-inducing processes include mesenchymal\u2013epithelial
transition factor (MET) amplification, epithelial\u2013mesenchymal transformation, phenotypic change from
NSCLC to small-cell lung carcinoma, and modifications in parallel signalling pathways. Current therapeutic
strategies to overcome these EGFR TKI resistance mechanisms focus on the inhibition or blocking of
multiple members of the ErbB family. Several molecules which target multiple ErbB receptors are being
investigated in NSCLC and other indications including afatinib, an ErbB Family Blocker, as well as dacomitinib
and lapatinib. Novel, non-quinazoline, EGFR inhibitors, that also target EGFR activating and resistance
(T790M) mutations, are currently under clinical development. Other therapeutic strategies include
inhibition of parallel and downstream pathways, using agents which target heat shock protein (HSP)90 orpoly (ADP-ribose) polymerase in addition to mammalian target of rapamycin (mTOR), monoclonal antibodies
against the insulin-like growth factor-1 receptor, and fulvestrant-mediated oestrogen receptor
regulation.
Conclusion: Improved understanding of mechanisms underlying resistance to EGFR TKIs emphasises the
importance of a genotype-guided approach to therapy. Elucidation of resistance mechanisms is indeed
crucial to target innovative therapeutic approaches and to improve the efficacy of anticancer regimes
in NSCLC