5 Questions for Nita Maihle, PhD

Nita Maihle, PhD, is a professor of Obstetrics, Gynecology and Reproductive Sciences, and director of a clinically oriented cancer research laboratory at Yale University, New Haven, Connecticut. She is listed as an inventor on 10 US patents in the fields of cancer therapeutics and diagnostics, is a cofounder of a biotechnology company, and serves on the National Cancer Institute’s Board of Scientific Counselors. Her main interest is in improving healthcare through the emergence of more precise diagnostic tests and the development of rationally designed, biologically targeted therapeutics.

1

What role does EGFR signaling play in normal cells?

The roles of EGFR [epidermal growth factor receptor] in normal cells are diverse and “primitive.” From the earliest multicellular organisms, one finds expression of EGF and its cognate receptors playing a fundamental role in such processes as cell division, survival, and differentiation. In humans, these roles have evolved to the regulation of complex interactions between cells.

2

How important is it in cancer development?

EGFR, in the form of a retroviral oncogene called v-ERBB, was one of the earliest human oncogenes to be identified. Through studies of this viral homolog we learned that mutant forms of the EGFR could induce cancer in diverse tissues.

We also learned that there are both ligand-dependent (via binding to soluble and/or membrane-bound growth factors, such as EGF, TGF-α [transforming growth factor], and amphiregulin, among others) and ligand-dependent mechanisms of EGFR signaling, the latter being particularly important in cell survival signaling, where EGFR’s interaction with integrin, another cell surface protein, is responsible for regulating alternative signal transduction pathways.

Overexpression of EGFR ligand transforming growth factor (TGF)-α can set off events that result in resistance to EGFR antibodies. Ub denotes ubiquitylation; CBL, E3 ubiquitin-protein ligase; SFK, Src family kinase; E2F1, transcription factor; P, phosphorylation; PCNA, proliferating cell nuclear antigen; PTEN, phosphatase and tensin homolog; STAT3, signal transducer and activator of transcription.

The mechanisms of resistance to EGFR TKIs can start with a mutant form of the receptor called EGFR variant III. T790M denotes threonine 790 mutation; IGF, insulin-like growth factor; AXL, tyrosineprotein kinase receptor UFO (AXL oncogene); IGFBP, insulin-like growth factor-binding protein.

Both graphics adapted from Wheeler DL, Dunn EF, Harari PM. Understanding resistance to EGFR inhibitors—impact on future treatment strategies. Nat Rev Clin Oncol. 2010;7:493—507.

3

What EGFR-targeted treatments are currently available?

In brief, so far, there are basically two broad categories of drugs targeting this receptor. The most notable to date are small-molecule tyrosine kinase inhibitors [TKIs] such as Tarceva and Iressa. The second are several monoclonal antibodies, including cetuximab and panitumumab, among others.

Many others are in the pipeline at major pharmaceutical and biotechnology companies. So far, these drugs have been approved by the FDA for the treatment of lung cancer, colorectal cancer, head and neck cancer, pancreatic cancer, and breast cancer, but further latestage clinical trials will see this list continue to expand.

4

What has been the key discovery relating to EGFR signaling in cancer in recent years?

A major discovery has been the utility of small-molecule EGFR/TKIs for the successful treatment of non—small cell lung carcinoma, based on the identification of specific EGFR mutations/ genotypes in tumor specimens from cancer patients.

This discovery has provided proof of concept for the importance of personalized medicine. That is, based on knowledge of the expression pattern, as well as the sequence of key oncogenes in human tumors, we can now use this information to direct molecularly targeted, highly effective new therapies in a side effect—sparing manner in cancer patients.

5

What is the main unanswered question with regard to EGFR signaling in cancer research or EGFR-targeted treatments?

Given the importance of this receptor family in the development of cancer, and the emerging pipeline of EGFR-targeted therapeutics, it has been paradoxical that most/all EGFR-based diagnostic tests for directing EGFR-targeted therapy—with the exception of sequencing for specific EGFR mutations—fail to predict responsiveness to the diverse drugs available targeting EGFR.

We have recently proposed that one reason for this failure is the existence of a number of different EGFR isoforms. As we learn more about these receptor isoforms, we will be able to develop isoform-specific tests that will allow us to better direct therapy using EGFR-targeted agents in cancer treatment.