Rethink of EGFR in Cancer With Its Kinase Independent Function on Board

Abstract

The epidermal growth factor receptor (EGFR) is one of most potent oncogenes that are commonly altered in cancers. As a receptor tyrosine kinase, EGFR's kinase activity has been serving as the primary target for developing cancer therapeutics, namely the EGFR inhibitors including small molecules targeting its ATP binding pocket and monoclonal antibodies targeting its ligand binding domains. EGFR inhibitors have produced impressive therapeutic benefits to responsive types of cancers. However, acquired and innate resistances have precluded current anti-EGFR agents from offering sustainable benefits to initially responsive cancers and benefits to EGFR-positive cancers that are innately resistant. Recent years have witnessed a realization that EGFR possesses kinase-independent (KID) pro-survival functions in cancer cells. This new knowledge has offered a different angle of understanding of EGFR in cancer and opened a new avenue of targeting EGFR for cancer therapy. There are already many excellent reviews on the role of EGFR with a focus on its kinase-dependent functions and mechanisms of resistance to EGFR targeted therapies. The present opinion aims to initiate a fresh discussion about the function of EGFR in cancer cells by laying out some unanswered questions pertaining to EGFR in cancer cells, by rethinking the unmet therapeutic challenges from a view of EGFR's KID function, and by proposing novel approaches to target the KID functions of EGFR for cancer treatment.

Validation of the 8th lung cancer TNM classification and clinical staging system in a German cohort of surgically resected patients

“…With advances in genomic analysis and targeted therapies, genetic differences even among tumors of the same histological subtype are becoming more significant than ever. A tumor mutation that responds well to available immunotherapies can mean a significant survival benefit that is independent of tumor stage [ 26 ], [ 27 ]. Developments in the field of cancer immunology have sparked discussions about incorporating tumorbiological characteristics into future staging systems, but so far no actual changes have been implemented.…”

Recent developments in anticancer kinase inhibitors based on the pyrazolo[3,4-d]pyrimidine scaffold

“…68 Mutations and aberrations in EGFR activity play an important role in many malignancies, including breast, lung, and oesophageal cancers, amongst others, making EGFR an attractive target for intervention. 69,70 Gefitinib, first characterised in 1996, was the first EGFR inhibitor to be approved by the FDA, for the treatment of NSCLC, in 2003. Further EGFR inhibitors, such as erlotinib, an anticancer drug used for breast and pancreatic cancers, and lapatinib followed soon after.…”

Discovery of a novel EGFR ligand DPBA that degrades EGFR and suppresses EGFR-positive NSCLC growth

“…These interaction levels are higher in tumour cells than in normal cells. 10,[39][40][41][42][43][44] DPBA may destabilize EGFR through interrupting these interactions. This may partially explain why DPBA showed specific toxicity towards tumour cells.…”