Project 4: P95HER2, Antitumor Immunity and the Efficacy of HER2-Directed Antibody Drug Conjugates

Breast cancers that overexpress the HER2 oncoprotein, called HER2+, aren't as common as other subtypes but can be more aggressive.

The development of trastuzumab in the early 2000s as an antibody-based targeted therapeutic for HER2+ breast cancer heralded a new era of precision medicine in cancer. Numerous trials have demonstrated dramatic efficacy of trastuzumab, and it has had enormous positive impact on outcomes.

Additional HER2-targeting antibody-based therapeutics have since been developed, including antibody-drug conjugates (ADCs) of trastuzumab that recognize the same HER2 epitope and deliver a cytotoxic payload when internalized. Trastuzumab deruxtecan (T-DXd) is one such ADC that has gained recent attention because of its striking efficacy in heavily pretreated metastatic disease.

However, even with these newer therapeutics, not all people with HER2+ breast cancer respond initially to HER2-targeting therapeutics, and many early responders eventually develop treatment-resistant recurrences. This represents a significant health crisis, since more than 250,000 people are living with HER2+ breast cancer in the United States.

While the potential mechanisms for cancer-cell intrinsic resistance to anti-HER2 therapy are numerous, emerging evidence suggests that a major recurrent event involves epitope loss or masking to prevent recognition of the HER2 target by therapeutic antibodies.

A striking example of this mechanism comes from the observation that up to 50% of metastatic therapy-resistant HER2+ breast cancers express a truncated form of HER2 that lacks nearly the entire extracellular domain yet remains highly active as a signaling molecule. This form of HER2 is called p95HER2. Because p95HER2 lacks most of the extracellular domain, it can't be recognized and targeted by trastuzumab and related therapeutic antibodies.

Our research team has discovered that in addition to evading antibody-based therapeutics, p95HER2 also exhibits properties that allow it to function differently from the canonical, full-length HER2 oncoprotein. Specifically, p95HER2 drives a unique program of tumor immune suppression that has the potential to impair the overall efficacy of anticancer therapeutics — it stops cancer treatments from working well.

As a result, expression of p95HER2 in breast cancer may present multiple therapeutic challenges. This research project will deepen our team's understanding of p95HER2 action and its impact on breast cancer pathobiology. It also will help inform new therapeutic concepts for overturning the effects of p95HER2.