Understanding Resistance to EGFR Inhibitors—Impact on Future Treatment Strategies

Deric L. Wheeler; Emily F. Dunn; Paul M. Harari

Disclosures
In This Article

Future Directions and Conclusions

The advancement of EGFR inhibitors for cancer therapy has moved rapidly in the broad context of oncology therapeutics. The fact that four new EGFR inhibitors (gefitinib, cetuximab, erlotinib, and panitumumab) received FDA approval for use in oncology in the space of less than 4 years, is a remarkable testament to the functional role of EGFR as a molecular target that regulates tumor cell behavior and response to treatment. Indeed, additional promising drugs with multitarget activity (including anti-EGFR action) are in active development or have received FDA approval in oncology, such as lapatinib. These new agents will enable the systematic evaluation of multitarget inhibition strategies, which include EGFR blockade, to affect tumor response in human cancers.

Despite rapid advances in EGFR oncology therapeutics over the past decade, substantial room for progress remains. Most cancer patients do not respond to EGFR inhibitor therapy, which implies intrinsic resistance. Even in those patients who do achieve a clear tumor response to EGFR inhibitors, the majority will eventually manifest disease progression, which implies acquired resistance. Improving our ability to identify the tumors that rely on EGFR signaling for their growth is critical to the optimal selection of patients for therapy. This concept is beautifully borne out by the EGFR mutation studies first reported in 2004 that identified activating mutations in EGFR that confer a high likelihood of response to the anti-EGFR TKIs.[74–76]

Alternative RTK pathways that are activated following EGFR inhibition is another area for investigation. These alternative pathways may bypass or evade inhibition of EGFR signaling, thereby enabling combinations of agents to simultaneously attack multiple molecular targets for cancer growth inhibition. Finally, the capacity of cancer cells to adapt to treatment suggests that additional mechanisms of resistance to EGFR inhibitors may have a key role in regulating tumor response, such as the induction of tumor/stromal interactions (angiogenesis), translocation of surface receptors to the nucleus, altered DNA damage response, and as yet undiscovered mutations. Advancing our knowledge of specific cellular and molecular mechanisms of resistance to EGFR inhibitor therapies will illuminate new strategies to improve this promising class of agents.

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