Mutations in the KRAS gene are a major cause of pancreatic cancer.
This gene plays a crucial role in controlling cell growth and survival, and when it mutates, it keeps promoting cell growth, leading to excessive multiplication and tumor formation.
Recently developed drugs that inhibit KRAS have shown promise for treating this form of cancer.
But, pancreatic cancer has a knack for developing drug resistance. Over time, the cancer finds ways to render most drugs ineffective.
How Cancer Outsmarts Drugs
Scientists believe they have identified a possible reason for this drug resistance. When the KRAS gene is inhibited, a group of genes known as ERBB, which lie upstream of KRAS, seem to become more active.
As KRAS goes down, ERBB goes up, triggering the activity of KRAS and other related genes, thus driving the cancer.
A Promising Drug Combination
In light of these findings, researchers at the University of California San Diego School of Medicine decided to experiment with a combination of KRAS and ERBB inhibitors.
Their study, published in Cancer Research, revealed this drug combination to be much more effective and less likely to trigger resistance than using the KRAS inhibitor alone.
The team now advocates for testing this combination in clinical trials with cancer patients.
“KRAS inhibitors could entirely revolutionize pancreatic cancer treatment,” commented Herve Tiriac, Ph.D., co-senior author of the study.
“However, we need extensive preliminary testing to optimize KRAS therapy, or else clinical trials may yield a lot of negative data.”
Confirming and Overcoming Resistance
The study was the first to show that human pancreatic cells treated with the KRAS inhibitor MRTX1133 do develop drug resistance and upregulate ERBB.
However, this resistance can be surmounted by using MRTX1133 along with Afatinib, an FDA-approved pan-ERBB inhibitor.
The combination of MRTX1133 and Afatinib also reduced the number of surviving cancer cells more than MRTX1133 alone.
Furthermore, this pair was more effective than combining MRTX1133 with other drugs targeting different molecules downstream of KRAS.
The pancreatic cancer cells were so vulnerable to the combination of MRTX1133 and Afatinib that the drugs interacted synergistically.
That is, the combined effect of both drugs was even greater than their individual impacts.
Testing in Animal Models
The researchers also tested this drug combination in mice with pancreatic cancer and found that those treated with both drugs lived significantly longer than those treated with just one.
The use of both human and mouse models, 2D cell cultures, 3D organoids, and in vitro and in vivo measurements added strength to the study.
“The synergy between MRTX1133 and Afatinib was remarkable, and we strongly urge clinical testing of this drug combination for pancreatic cancer patients,” said Andrew Lowy, MD, co-senior author of the study.
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The study was published in Cancer Research. Follow us on Twitter for more articles about this topic.
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