Potential new drug for some patients with treatment-resistant lung cancer

October 20, 2013

The investigational drug AZD9291, a third-generation EGFR inhibitor, showed promise in preclinical studies and provides hope for patients with advanced lung cancers that have become resistant to existing EGFR inhibitors, according to results presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held Oct. 19-23.

Mutations in the growth factor gene EGFR are present in about 10 to 15 percent of with the most common form of lung cancer, non-small cell lung cancer (NSCLC). Most NSCLCs harboring these EGFR mutations, called activating mutations, respond to the EGFR inhibitor drugs erlotinib and gefitinib. A majority of such cancers, however, develop resistance to these drugs within about nine to 11 months. In many cases, this is due to the cancer cells acquiring a second mutation called EGFR T790M, also known as the "resistance mutation."

"There are no approved therapies to treat lung cancer patients who develop the second mutation in the EGFR that stops the currently available medicines from working," said Susan Galbraith, M.D., Ph.D., head of the Oncology Innovative Medicines Unit at AstraZeneca. "The innovative breakthrough was finding a series of molecules that could target both the activating and resistance mutant forms of EGFR more potently than normal EGFR, which led to development of the new EGFR kinase inhibitor, AZD9291.

"AZD9291 is highly active in preclinical models and is well tolerated in animal models. It inhibits both activating and resistant EGFR mutations while sparing the normal form of EGFR that is present in normal skin and gut cells, thereby reducing the side effects encountered with currently available medicines," she added.

The AstraZeneca scientists first showed that AZD9291 potently inhibited cells with mutant EGFR, grown in lab dishes. They then tested the drug on mice bearing lung tumors with activating mutations and mice bearing with resistance mutations. AZD9291 showed substantial tumor shrinkage in both groups of mice after 14 days of treatment. After 40 days, the researchers found no visible tumors in these mice, and this effect was sustained for more than 100 days. They also observed similar tumor shrinkage in mice that were genetically modified to develop tumors bearing both the activating and resistance mutations.

When the investigators analyzed blood samples collected from the treated mice, they identified a breakdown product of the parent compound AZD9291, which they called AZ5104, circulating in blood in addition to AZD9291. They then found that AZ5104 is also a potent inhibitor of activating and resistance EGFR mutations, and speculated that this may contribute to the efficacy seen after dosing with AZD9291.

Using data from blood analyses of mice, the researchers then developed a mathematical model to evaluate the dynamics of conversion of AZD9291 to AZ5104 and cumulative tumor-inhibitory effects. These experiments helped them determine the potentially effective doses of AZD9291 for patients with NSCLC harboring both activating and EGFR .

"Findings from have recently been translated to the clinic, where the drug has already demonstrated in patients and has been well tolerated, with low rates of side effects," said Galbraith. "The degree of response to treatment with AZD9291 in such a short period of time is very exciting. This new drug has the potential to provide new treatment options for patients in this setting."

Explore further: Molecular marker predicts patients most likely to benefit longest from two popular cancer drugs

More information: Galbraith is an employee of AstraZeneca, which sponsored this study.

Related Stories

Molecular marker predicts patients most likely to benefit longest from two popular cancer drugs

September 5, 2013
Johns Hopkins scientists have identified a molecular marker called "Mig 6" that appears to accurately predict longer survival—up to two years—among patients prescribed two of the most widely used drugs in a class of anticancer ...

Some patients with treatment-resistant colorectal cancers may have a new option

June 2, 2013
A subset of colorectal cancers responds to anti-epidermal growth factor receptor (anti-EGFR) therapies, but develops resistance within months. Among cancers that develop resistance to anti-EGFR therapy, some showed overexpression ...

Tumors with ALK rearrangements can harbor more mutations

April 22, 2013
The identification of potentially targetable kinase mutations has been an exciting advancement in lung cancer treatment. Although the mutations driving many lung carcinomas remain unknown, approximately 50 percent of lung ...

Interference with cellular recycling leads to cancer growth, chemotherapy resistance

September 18, 2013
Overactivity of a protein that normally cues cells to divide sabotages the body's natural cellular recycling process, leading to heightened cancer growth and chemotherapy resistance, UT Southwestern Medical Center researchers ...

EGFR mutation not prognostic factor in non-small cell lung cancer

January 15, 2013
Recent studies have demonstrated that molecular-targeted agents, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), may prolong survival of selected patients based on tumor biomarkers. The presence ...

Patients with EGFR exon 20 insertions have poorer prognosis

January 15, 2013
Exon 20 insertions are the third most common family of epidermal growth factor receptor (EGFR) mutations found in non–small-cell lung cancer (NSCLC). Little is known about cancers harboring these mutations aside from their ...

Recommended for you

Study may explain failure of retinoic acid trials against breast cancer

July 25, 2017
Estrogen-positive breast cancers are often treated with anti-estrogen therapies. But about half of these cancers contain a subpopulation of cells marked by the protein cytokeratin 5 (CK5), which resists treatment—and breast ...

Physical activity could combat fatigue, cognitive decline in cancer survivors

July 25, 2017
A new study indicates that cancer patients and survivors have a ready weapon against fatigue and "chemo brain": a brisk walk.

Breaking the genetic resistance of lung cancer and melanoma

July 25, 2017
Researchers from Monash University and the Memorial Sloan Kettering Cancer Center (MSKCC, New York) have discovered why some cancers – particularly lung cancer and melanoma – are able to quickly develop deadly resistance ...

New therapeutic approach for difficult-to-treat subtype of ovarian cancer identified

July 24, 2017
A potential new therapeutic strategy for a difficult-to-treat form of ovarian cancer has been discovered by Wistar scientists. The findings were published online in Nature Cell Biology.

Immune cells the missing ingredient in new bladder cancer treatment

July 24, 2017
New research offers a possible explanation for why a new type of cancer treatment hasn't been working as expected against bladder cancer.

Anti-cancer chemotherapeutic agent inhibits glioblastoma growth and radiation resistance

July 24, 2017
Glioblastoma is a primary brain tumor with dismal survival rates, even after treatment with surgery, chemotherapy and radiation. A small subpopulation of tumor cells—glioma stem cells—is responsible for glioblastoma's ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.