In all communications, including cell communication, context matters. And yet, when cell communication takes a cancerous turn, context often remains unclear. This is a big problem in the field of cancer therapeutics, which uses drugs to steer misdirected cell communication toward healthful ends.
To capture context—and to learn how to alter cell communication more effectively—scientists based at the Institute of Cancer Research (ICR) looked at dynamic cell signaling, that is, cell signaling that varies depending on the tissue background. The scientists hoped to shed light on why gene-targeting drugs often work differently in people whose tumors have the same genetic faults.
The scientists, led by Udai Banerji, PhD, deputy director of the ICR’s Drug Development Unit, established that in cells from lung, bowel, and pancreatic cancers, there are stark biological differences in how cancer cells of different tumor types respond to gene-targeted drugs. These findings suggest that the genetics of a patient’s cancer may not always be enough to tell whether the patient will respond to a treatment.
“We found that cells from different cancers responded quite differently to drugs targeting the same genetic faults—suggesting that if someone’s tumor has a particular genetic fault, we can’t automatically assume that a drug targeting that fault will work for them, said Banerji. “Our new study suggests that we need to take cancer type into account when designing clinical trials testing the benefit of treatments targeting specific genetic changes—and that we no longer group people participating in clinical trials by the genetic faults in their tumor alone.”
Banerji and colleagues looked at the different cancer cell types in the lab and measured changes in “on and off switch” molecules that can alter cellular communication. The scientists found that drugs that blocked the common cancer gene PI3K, including an experimental drug discovered at the ICR called pictilisib, had varying effects in different cancer types.
Details appeared July 1 in the journal Molecular Cancer Therapeutics, in an article titled, “Differences in Signaling Patterns on PI3K Inhibition Reveal Context Specificity in KRAS-Mutant Cancers.” This article describes how Banerji and colleagues used an antibody-based phosphoproteomic platform to study changes in 50 phosphoproteins caused by seven targeted anticancer drugs in a panel of 30 KRASMT cell lines and cancer cells isolated from 10 patients with KRASMT cancers.
“We report for the first time significant differences in dynamic signaling between colorectal cancer and NSCLC cell lines exposed to clinically relevant equimolar concentrations of the pan-PI3K inhibitor pictilisib including a lack of reduction of p-AKTser473 in colorectal cancer cell lines and lack of compensatory increase in p-MEK in NSCLC cell lines,” the article’s authors wrote. “Differences in rewiring of signal transduction between tumor types driven by KRASMT cancers exist and influence response to combination therapy using targeted agents.”
One of the ways PI3K works is to flip the off switch on a related protein, AKT, to stop tumor growth—but in this study, bowel cancer cells were less likely than lung cancer cells to switch off AKT in response to pictilisib.
In the current study, which looked at the response to pictilisib in detail, the scientists found that the drug triggered an increase in another protein switch, called MEK, in three out of seven samples taken from people with bowel cancer, but in none of the three samples from lung cancer patients.
The study was done in cells in the lab, and larger studies will be needed to uncover the signaling changes in response to targeted drugs in more detail. But the researchers believe the findings will affect the outcome of ongoing clinical trials—and the results are already influencing the design of early-stage trials testing the benefit of new drugs blocking the KRAS gene.
In future, the work could also lead researchers to look back at existing treatments that were deemed to have “failed,” and reassess their benefit in different cancer types.
“Precision medicine has driven huge advances in cancer treatment over the last two decades, giving some patients months or years of extra life with far fewer side effects than traditional chemotherapy,” commented Paul Workman, the ICR’s chief executive. “This new study brings nuance to the paradigm of precision medicine, and shows that the story isn’t quite as straightforward as matching a drug to a cancer’s genetics.”