Wednesday , September 28 2022

UC San Francisco scientists recognize 'Achilles heel' of drug-resistant cancers


UC San Francisco scientists have figured out why some lung cancers become drug-resistant after initially responding to targeted therapies. In the process, they devised a new two-pronged approach that yields a effective treatment for these cancers in the laboratory and holds the precision medicine for the future, they said. The findings are detailed in a new study. 26 in the journal Nature Medicine.

Cancer Outsmarts Precision Therapy

Certain lung cancers are characterized by mutations in a protein called EGFR. Normally, EGFR acts as the 'on / off' switch in a complex molecular circuit that tells the cell when it is appropriate to grow and divide (on), and when it's not (off). Although the circuit usually knows when to shut itself off, the mutant forms of EGFR found in the lung cancer are stuck in the 'on' position. This leads to abnormal cell proliferation and transforms healthy tissue into cancer.

Although scientists have developed designer drugs that target mutant EGFR and activate the tumor's self-destruct mechanism, these curative effects rarely endure. Even after three successive generations of increasingly potent precision therapies that are specifically targeted in the mutant protein, the results are always the same: up to 18 months of remission followed by relapse. And when the tumor returns, it's drug resistant and more aggressive than ever

"The promise of precision medicine is that doctors can treat patients using drugs that target a patient's unique form of cancer. But for all the hype, precision medicine is often its potential to survival. be solved, "said Sourav Bandyopadhyay, PhD, UCSF associate professor of bioengineering and therapeutic sciences and senior author of the new study.

Bandyopadhyay says that the reason is an gap separating precision therapy and its actual efficacy is because tumors are clever. They're able to rewire their internal circuitry and devise new strategies to promote their own survival, even after initially succumbing to the shock of targeted therapy. Although researchers have shown that the drugs continue to inhibit EGFR activity after tumors become resistant, the self-rewiring means that the tumor is no longer dependent on the mutant protein for its continued survival. Bandyopadhyay wanted to know why

Aurora Emerges as Cancer's 'Achilles Heel'

To identify drivers of drug resistance, the researchers took multiple cancer cell lines with mutated EGFR and treated them in the culture dish with osimertinib or rociletinib, third-generation drugs that target the mutant protein. Osimertinib is FDA approved for treatment of EGFR-mutated non-small cell lung cancer. Although the cancer cells were seen in the drugs after administered, they reemerged just six weeks later to resist both.

After the cancer cells stopped responding to EGFR drugs, the researchers tested 94 additional drugs to see if any could reverse the acquired resistance. They discovered that drugs targeting a protein called Aurora Kinase A, when combined with osimertinib or rociletinib, killed the cancer cells once and for all

Similar results were observed when the researchers transplanted drug-resistant tumors from lung cancer patients in live mice. Although the tumors continued to grow when the mice were treated with EGFR drugs alone, the two-pronged approach in both proteins were targeted simultaneously due to the tumors to shrink with no observed toxicity to the mice.

"It's a fundamentally new pathway for resistance to emerge," said Bandyopadhyay, who is also a member of the UCSF Helen Diller Family Comprehensive Cancer Center.

Aurora Helps Cancer Escape Death

The researchers found that Aurora does not drive growth on its own. That's why a treatment regimen targeting only Aurora failed to thwart the cancer's progress. What the Aurora provides is a way for malignancies to escape death.

Osimertinib and rociletinib work by shutting off mutant EGFR. This not only slows the cancer's growth, it also triggers its self-destruct circuitry, causing tumors to wither away and die. That is, until the tumor rewires itself and activates Aurora

Aurora serves as cancer's escape hatch Acting independently of EGFR, Aurora silences the cell's suicide circuits, regardless of what EGFR is telling these circuits to do, thus ensuring cancer's continuous survival. By targeting Aurora and mutant EGFR in tandem, the researchers effectively sealed the cancers fate by sealing its lone escape hatch.

A Clinically Significant Discovery

Not only did the researchers discover a new way to target drug-resistant tumors, they also identified a biomarker that could tell clinicians whether the lung cancer they've been susceptible to joint therapies that both EGFR and Aurora are targeted.

The researchers found elevated levels of a protein called TPX2 in biopsies of advanced stage, drug-resistant lung cancers taken from multiple patients. They believe that TPX2, which is known to activate Aurora kinase, may help clinicians identify when a patient's tumor will succumb to the joint targeted therapies.

The next step, says Bandyopadhyay, is going to get its two-pronged approach and the TPX2 biomarker approved for clinical trials.

"As more and more patients are progressing on third-generation EGFR inhibitors, our work delineates a new mechanism of resistance that appears in the majority of patients and is targetable using the current Aurora kinase inhibitors. We hope this work re-invigorates pharma interest We believe that this class of molecules has incredible power when combined with other targeted therapies, which is not how they have historically tested. We hope that our results are new trials of initiation catalyze so that patients with mutant EGFR may reap the benefits of our combined approach. "


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