A team of scientists from UC San Francisco have recently published their research findings about why certain lung cancers become drug-resistant even after originally responding to targeted therapies. The study, which was published in Nature Medicine just recently, shows how the researchers created an innovative two-pronged approach that produces an effective method of treatment for these cancers. This method also represents a breakthrough in the future of precision medicine.

Referred to as the two-pronged approach, this drug combo represents a revolutionary new way to attack drug-resistant tumors. While scientists have already created designer drugs that target mutant EGFR and activate the tumor’s self-destruct machinery, these curative effects rarely endure. The study shows that when these designer drugs are combined with a specific kind of cell cycle inhibitors, they are able to permanently kill drug-resistant cancer cells.

Cancer and Precision Therapy

Some types of lung cancers are characterized by EFGR mutations. EFGR is a protein which acts as the “on/off” switch in a complex molecular circuit. Its role is signal to the cell when it is time to grow and divide and when it is not. The mutant forms of EFGR are stuck in a position where it is continually growing and dividing. As a result, the abnormal cell proliferation changes what is supposedly healthy tissue into cancer.

While researchers have already developed designer drugs which are intended to address these EFGR mutations and activate the self-destruct system in tumors, the curative effects of these designer drugs tend to be short-lived. This means that even with three successive introduction of precision therapy which are designed to target EFGR mutations, the results remain the same: months of remission, followed by a relapse.

When the tumor returns, it is more aggressive and more drug-resistant than it was before. The self-rewiring capacity of these cancer cells implies that the tumor no longer depends on the mutant protein to be able to continuously survive. Over time, these tumor cells are able to rewire themselves so are able to continue growing even without the presence of the mutated protein produced by the mutated protein.

Precision medicine has shown promise when it was first introduced as a form of cancer treatment. However, because of the drug-resistant effects on EFGR mutations, the treatment does not live up to its expectations and is essentially worthless in this area of study. According to experts, the lack of effectiveness of precision therapy is due to the ability of tumors to rewire their internal mechanisms and adopt new strategies to ensure their survival. This means that although they may initially be defeated by targeted therapy, their self-rewiring abilities ensures their continued survival months after the treatment was administered.

Aurora: A New Weakness of Drug-Resistant Tumors

The research team in the newly published study looked into various cancer cell lines with EFGR mutations and treated them in a culture dish with two types of third-generation drugs that are intended to address the mutated protein. One of this is osimertinib, an FDA-approved drug which is used in the treatment of EGFR-mutated non-small cell lung cancer. The other one is rociletinib, a drug which is designed by Clovis Oncology to treat non-small cell lung carcinomas with a particular mutation that failed in phase 3 testing.

When the cancer cells became resistant to the two drugs, the researchers then introduced 94 more types of drugs to determine whether they can help reverse the newly-acquired resistance of the cancer cells. This allowed them to discover that drugs which are designed to target Aurora Kinase A, a type of protein, killed the cancer cells permanently.

They researchers then looked into observing the effect of the combination drug therapy in a living model, so they transplanted drug-resistant tumors into mice. The same results were obtained when cancer cells were transplanted into live mice. The tumors continued growing when EGFR drugs were used on their own. In the mice that were treated with EGFR inhibitors on their own, the tumors continued to develop and grow, but the two-pronged approached that were used in other mice test subjects promoted tumor shrinkage.

When the two-pronged approach was used, the tumors then shrunk without any observable toxicity. The researchers then appropriately called the protein Aurora Kinase A as the “Achilles’ heel” of cancer cells. This is a groundbreaking study because Aurora Kinase A has never been associated before with drug resistance in cancer cells. The researchers were able to determine that Aurora Kinase A, on its own, does not drive tumor growth. What it does, instead, is to offer a way in which cancer cells can escape death.

The oncology community is already quite familiar with Aurora kinases. In fact, earlier this year, Eli Lilly regained possession of an Aurora kinase A inhibitor that it had originally created by acquiring AurKa Pharma in a deal that is estimated to reach up to $575 million. Lilly is creating AurKa’s lead asset, AK-01, in solid tumors. Other pharma companies, however, have found difficulty in developing and testing Aurora kinase inhibition.

Alisertib, for instance, rose to prominence in 2008 due to Takeda’s $8.8 billion acquisition of Millennium Pharmaceuticals. However, the drug was unsuccessful in a late-stage lymphoma trial, leading the company to halt its development. Aurora Kinase has also never been associated with drug-resistant cancers, so the research essentially represents a new approach when it comes to this field.

Two-Pronged Approach

Aurora Kinase A essentially serves as a way for cancer cells to escape death. The two drugs osimertinib and rociletinib are able to shut off EGFR mutations to slow down the growth of the tumor and trigger its self-destruct mechanism so that the cancer cells can die. However, because of the ability of cancer cells to rewire itself, Aurora Kinase A gets activated and saves them from a permanent death while also imbuing them with drug-resistant capabilities.

Aurora Kinase A works on its own, silencing the suicide circuits of mutated EGFR, even though the cell itself is already on its way to self-destruction. This protein thus ensures that continued survival of cancer cells. By using a two-pronged approach in their study, the researchers were hence able to ensure the permanent death of cancer cells by eliminating their escape route. This combined approach can mean a revolutionary treatment design for cancer patients.

TPX2: A Biomarker for the Two-Pronged Approach

The researchers were not only able to find a new method for treating drug-resistant cancer, they were also able to identify a biomarker which would tell clinicians whether the lung cancer that is under observation would be susceptible to the two-pronged approach, which involves a combined therapy that targets both EGFR mutations and Aurora Kinase A. This biomarker is known as TPX2, another type of protein.

Their findings showed that there are elevated levels of TPX2 in biopsies of certain advanced stage, drug-resistant lung cancers. These samples were taken from several patients who have late-stage, drug-resistant lung cancer. The researchers believe that TPX2, which has been previously shown to have a role in activating Aurora Kinase A, will allow clinicians to determine when the patient’s tumor will respond well to the two-pronged approach.

The team is now in the initial steps of getting approval for clinical trials using the two-pronged approach and the TPX2 biomarker. They are also hoping that the study would reinvigorate more interest in cell cycle inhibitors, specifically Aurora kinase inhibitors. They believe that this class of molecules show astounding potential when integrated with other targeted therapies, especially because this is not how they have been used in previous tests.

Significance

Sourav Bandyopadhyay, one of the senior authors for the research reiterated the following: “As more and more patients are progressing on third-generation EGFR inhibitors, our work delineates a new mechanism of resistance that appears to occur in the majority of patients and is targetable using existing Aurora kinase inhibitors. We hope this work re-invigorates pharma interest in cell cycle inhibitors such as Aurora kinase inhibitors.

We believe that this class of molecules has incredible power when combined with other targeted therapies, which is not how they have been tested historically. We hope that our results catalyze the initiation of new trials so that patients with mutant EGFR may reap the benefits of our combined approach.”

They also said that they have high hopes that combination approach that they have developed will help revive interest in Aurora kinase inhibitors. Precision medicine’s promise to treat patients with drugs that target the only form of cancer of the patient initially failed to deliver because of the ability of cancer cells to become drug-resistant. The researchers also hopes that this new discovery will be able to resolve the unfortunate clinical reality of precision medicine. In the process, the researchers also believe that this new approach will yield an effective treatment for drug-resistant lung cancers.