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Helen Diller Family Comprehensive Cancer Center

Cancer Researchers ID 'Achilles Heel' of Drug-Resistant Tumors

Discovery Points the Way Towards New Strategy for Precision Cancer Therapy

By Jason Alvarez | UCSF.edu | November 26, 2018

Cancer Researchers ID 'Achilles Heel' of Drug-Resistant Tumors

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 an effective treatment for these cancers in the laboratory and holds tremendous promise for the future of precision medicine, they said. The findings are detailed in a study published Nov. 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’s appropriate to grow and divide (on), and when it’s not (off). Though the circuit generally knows when to shut itself off, the mutant forms of EGFR found in lung cancer are stuck in the ‘on’ position. This leads to abnormal cell proliferation and transforms healthy tissue into cancer.

Sourav Bandyopadhyay, PhD, senior author of the study.

Though scientists have developed designer drugs that target mutant EGFR and activate the tumor’s self-destruct machinery, these curative effects rarely endure. Even after three successive generations of increasingly potent precision therapies that specifically target 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 it allows doctors to treat patients using drugs that target a patient’s unique form of cancer. But for all the hype, precision medicine often fails to live up to its potential. It’s an unfortunate clinical reality that needs to 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 there’s a gap separating precision therapy’s promise 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. Though researchers have shown that these drugs continue to inhibit EGFR activity after tumors become resistant, the self-rewiring means that the tumor is no longer reliant 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 either osimertinib or rociletinib, third-generation drugs that target the mutant protein. Osimertinib is FDA approved for the treatment of EGFR-mutated non-small cell lung cancer. Though the cancer cells appeared to die off after the drugs were administered, they reemerged just six weeks later resistant to both. 

 

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