Is It Possible to Build a Resistant-Proof Targeted Cancer Drug?

Our lab is trying to do just that by probing lung tumors through the lens of patient-derived xenografts

Nearly three decades ago, the approval of Herceptin helped to usher in one of the most successful eras in cancer treatment. Though not the first monoclonal antibody to reach the market, Herceptin is among the most successful, giving an estimated 3 million women with Her2 positive breast cancer a lifeline. Today, there are more than 100 targeted therapies for many kinds of cancer that work in much the same way as Herceptin by hitting particular mechanisms used by tumors to grow or survive.  

On the face of it, targeted therapies seem like a perfect solution for cancer. Fire away at the unique vulnerabilities of cancer cells, often based on their genetic mutations, without harming normal cells. However, many cancers that initially respond to targeted therapies eventually learn to repel them.  When patients move on to a new targeted therapy the same pattern eventually occurs.

Overcoming targeted drug resistance is one of the biggest challenges for patients with cancer. Fortunately, scientists are making headway in figuring out how to overcome this, including at Charles River where scientists are studying resistance patterns in lung tumors.

Due primarily to tobacco, lung cancer remains the leading cause of cancer-related deaths worldwide—18% of the total—in 2022, the last year for which figures are available. Most of those deaths are from non-small cell lung cancer (NSCLC), which represents 85% of all lung cancer cases. Along with chemotherapy, radiation and most recently immunotherapy, targeted therapy is a recommended treatment option for lung cancers. There are several different ways targeted therapies are applied in lung cancer, and more than a dozen lung cancer mutations that are the targets of these drugs, with EGFR the oncogenic driver of tumor growth in around 30 percent of NSCLC. Today, both monoclonal antibodies (mAbs) and the small molecule tyrosine kinase inhibitors or TKI are approved for first-line targeted therapies against EGFR mutations in NSCLC patients.

Tyrosine kinases are of particularly importance because they influence multiple stages of tumor development. However, despite the overall good response towards the EGFR mutation, TKI´s acquired resistance still occurs in most patients after 9-14 months of therapy. Acquired resistance deprives patients of the long-term benefits of targeted therapies.

One of the ways that tumors provoke these streaks of drug resistance is by over-activating EGFR in malignant cells. But there are numerous other mechanisms of acquired resistance towards EGFR-TKIs ranging from secondary mutations in the EGFR gene to amplification or overexpression of molecules within the EGFR signaling cascade like MET or hepatocyte growth factor (HGF).

PDX lung cancer models can help us understand drug resistance

So, what can we do to overcome acquired resistance? One way is to use preclinical tools to study their development. New drugs are also needed badly that can overcome those mechanisms that empower tumors to fight back after being targeted.

Toward that end, Charles River has developed three NSCLC PDX lines carrying an acquired resistance towards gefitinib (also known as Iressa), a highly selective EGFR inhibitor and among the first targeted therapies to be approved for lung cancer. The resistance developed under constant treatment pressure over several months in tumor-bearing animals. The three lines emerged from three different animals and depicted different escape mechanisms to induce regrowth in the presence of a clinically relevant dose of gefitinib.

All three sublines depict a specific mutational and gene expression pattern that shows how tumor cells even within one tumor develop different strategies to escape the drug pressure. These PDX models were then further characterized by assessing in vivo sensitivity against cetuximab, a chimeric anti-EGFR antibody that is used to treat multiple cancers including lung cancer. The characterization included assessment of tumor growth over time, and proteomic and metabolomic analyses.

Interestingly, the three sublines showed different sensitivity patterns towards cetuximab, reflecting the complex interplay of different signaling pathways during the development of drug resistance. The proteomic analyses revealed an upregulation of proteins that are involved in epithelial-mesenchymal transition (EMT), bad prognosis or resistance in general.  EMT is described as one of the major escape mechanisms in solid cancer while the epithelial nature of the cell is changing towards another cell type (mesenchymal) that expresses different proteins on their surface and become "invisible” to targeted drugs. The upregulated proteins identified might help to identify new treatment options that will support the clinical decision making. These proteins can be targeted as well and drugs that bind to those EMT related proteins are currently under investigation.  

These kind of data sets lead to a better understanding of the evolution of acquired resistance and the tumor lines established will serve as research tools to develop next-generation compounds improving the life expectancy of NSCLC patients with acquired resistance. It’s about time that we built resistant proof therapies that deadly tumors can’t outsmart. For EGFR we are now at the third generation of compounds that overcome the resistance developed in the generation before. Stay tuned for new developments.