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.

Keywords: EGFR; cancer; cell survival; kinase independent function; mitophagy.

Figure 1

Known kinase-independent functions of EGFR in cancer cells. Currently known kinase-independent (KID) functions of EGFR locate at three functional domains of cancer cell. One is in the plasma membrane where EGFR interacts with SGLT1, Xc⁻, fatty acid synthase (FASN), and the mTORC2 complex to support transportation of glucose, cystine, de novo fatty acid synthase, and repressing mitophagy, respectively. The second function domain is the endosomal autophagy machinery where kinase inactive EGFR promotes pro-survival autophagy. The third domain is the mitochondrial domain where kinase inactive EGFR interacts with PUMA to inhibit apoptosis. KID-EGFR is oncogenic and pro-survival.

Figure 2

A model of two functional statuses of EGFR in cancer cells. The kinase activatable EGFRs are mainly involved in promoting cell growth, and the kinase unactivatable EGFRs, which are blocked from autocross-phosphorylation by interacting proteins, are mainly in charge of promoting oncogenic cell survival.

Figure 3

A hypothesis pertaining to EGFR's divergent roles in regulating growth vs. survival of cancer cells in relevant to TKI resistance. (A) In cancer cells expressing kinase-activating mutations, the role of EGFR is shifted toward its kinase-dependent functions, which sensitizes these cancers cells to TKI. (B) In cancer cells over-expressing wild type EGFR, the role of EGFR is shifted toward its kinase-independent functions, which promotes the progression of cancers rather desensitizes these cancers to TKI. (C) At situation of TKI treatment, the role of EGFR is also tilted toward its kinase-independent functions that allows cancer cells to survive and develop alternative growth-promoting mechanisms to counteract with TKI's inhibitory effect.