Improving drug options for colorectal cancer patients

Date:
December 14, 2021
Source:
Salk Institute
Summary:
Patients with colorectal cancer were among the first to receive
targeted therapies. These drugs aim to block the cancer-causing
proteins that trigger out-of-control cell growth while sparing
healthy tissues. But some patients are not eligible for
these treatments because they have cancer-promoting mutations
that are believed to cause resistance to these drugs. Now,
physician-scientists have used computer modeling and cell studies
to discover that more patients may be helped by a common class of
targeted therapies than previously thought.



FULL STORY ========================================================================== Patients with colorectal cancer were among the first to receive targeted therapies. These drugs aim to block the cancer-causing proteins that
trigger out-of-control cell growth while sparing healthy tissues. But
some patients are not eligible for these treatments because they have cancer-promoting mutations that are believed to cause resistance to
these drugs.


==========================================================================
Now, Salk Assistant Professor and physician-scientist Edward Stites has
used computer modeling and cell studies to discover that more patients
may be helped by a common class of targeted therapies than previously
thought. The findings were published December 14, 2021, in Cell Reports.

"Colorectal cancer patients who have tried all of the standard treatment options but still seen their cancer progress are in need of new
options. Our study suggests that one already available targeted therapy
could benefit up to 12,000 additional colon cancer patients every year,"
says Stites, the paper's senior author. "Our findings are pre-clinical,
and we hope this research will motivate clinicians to develop clinical
trials that further examine our results." Stites was interested in
examining drugs that target a protein called EGFR (epidermal growth
factor receptor). EGFR is known to drive a subset of a number of different cancer types, including lung cancer and colorectal cancer.

In 2004, the US Food and Drug Administration (FDA) approved cetuximab,
the first drug to block EGFR activity in colorectal cancer. Since then,
other drugs that target EGFR also have received approval. But from the
early development of these drugs, doctors believed that patients with
a mutation in any one of the family of proteins known as RAS would
not respond to EGFR drugs. Therefore, whenever molecular testing of a
patient's tumor revealed a RAS mutation, the patient was not offered
these targeted therapies.

Earlier research by the Stites lab suggested that not all RAS mutations
act in the same manner, and was able to explain one well-known, but
poorly understood, exception to the rule. In the new study, the team
combined computational and experimental approaches to use this new
explanation to find more RAS mutations that should not cause resistance
to the EGFR drugs.

The researchers used cells from cancers that were identical except for
specific RAS mutations. This allowed them to compare how each specific
mutation influenced the response to EGFR-inhibiting drugs. They found
that some RAS mutations did not prevent the drugs from working. These experiments also allowed them to validate their computational studies,
which helps establish how new computational methods could contribute to improving treatment options for cancer patients.

The investigators also examined how well different RAS mutants bound
to another protein, called NF1. Stites' previous mathematical models
hinted that NF1 could play a key role in the cells' response to targeted
drugs. In their new studies they revealed that the RAS mutants that do
not bind NF1 well retain sensitivity to EGFR drugs, while the RAS mutants
that bind NF1 well are resistant to EGFR drugs. This relationship to
EGFR drugs was not originally apparent, but the computational modeling
was able to uncover it from within the available and varied data.

Ultimately, the investigators identified 10 distinct RAS mutations that
do not preclude the use of EGFR inhibitors. Many of the drugs that would
work for these mutations are already approved by the FDA for other uses,
which means that doctors could start prescribing them for their patients
"off label" even before clinical trials are conducted.

Stites, who holds the Hearst Foundation Developmental Chair, stresses
that this study also helps to validate the mathematical and computational methods developed by his team. "Models can solve scientific problems that traditional methods cannot," he says. "We hope that future clinical trials
will help identify the magnitude of benefit as well as whether all the
RAS mutations we identified are equally sensitive to the EGFR-inhibiting
drugs and how other mutations in addition to RAS may influence the
strength of the response." The first author of the paper is Thomas
McFall, a former postdoctoral fellow at Salk who is now at the Medical
College of Wisconsin.

This work was supported by National Institutes of Health grants
K22CA216318, DP2AT011327, T32CA009370 and P30CA014195 and Department of
Defense grant W81XWH-20-1-0538.

========================================================================== Story Source: Materials provided by Salk_Institute. Note: Content may
be edited for style and length.


========================================================================== Journal Reference:
1. Thomas McFall, Edward C. Stites. Identification of RAS mutant
biomarkers
for EGFR inhibitor sensitivity using a systems biochemical
approach. Cell Reports, 2021; 37 (11): 110096 DOI:
10.1016/j.celrep.2021.110096 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211214135056.htm

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