Episode 427: Pharmacology 101: Resistance Pathways

“A good way of thinking about this is this is the survival of the fittest clone. There could be a portion of a cancer that naturally has some resistance or ability to survive a particular drug. And over time, as the other cells around it are dying off, that particular clone is able to replicate and continue to survive in the face of that drug therapy and eventually take over as being the fittest clone. At that point, we’re often seeing disease progression,” Danielle Roman, PharmD, BCOP, manager of clinical pharmacy services at the Allegheny Health Network Cancer Institute in Pittsburgh, PA, told Jaime Weimer, MSN, RN, AGCNS-BS, AOCNS^®, manager of oncology nursing practice at ONS, during a conversation about resistance pathways. 

Music Credit: “Fireflies and Stardust” by Kevin MacLeod

Licensed under Creative Commons by Attribution 3.0 

Earn 0.5 contact hours of nursing continuing professional development (NCPD), including 30 minutes of pharmacotherapeutic content, by listening to the full recording and completing an evaluation at courses.ons.org by August 7, 2027. Roman has served on advisory boards for Genetech, Pfizer, Regeneron, and Daiichi Sankyo and received honoraria payments from Pharmacy Times and Decera for faculty lectures. These financial relationships have been mitigated. ONS is accredited as a provider of nursing continuing professional development by the American Nurses Credentialing Center’s Commission on Accreditation.

Learning outcome: Learners will report increased knowledge related to resistance pathways in oncology care.

Episode Notes 

• Complete this evaluation for free NCPD. 
• ONS Podcast™ episodes:
  • Pharmacology 101 series
  • Episode 423: Pharmacology 101: Interaction Pathways
  • Episode 406: Drug Resistance Biomarkers and Their Impact on Cancer Treatment Choices
• ONS Voice articles:
  • Predictive and Diagnostic Biomarkers
  • Scientists Identify Protein Implicated in Tumor Growth, Treatment Resistance
• ONS book: Guide to Cancer Immunotherapy (second edition)
• Genomics and Precision Oncology Learning Library
• ONS Biomarker Database
• Pharmacogenomics Huddle Card
• CancerQuest: Cancer Drug Resistance
• National Comprehensive Cancer Network
• OncoKB.org
• Research To Practice

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Highlights From This Episode

“As we look at drug resistance, this is the concept that cancer cells are no longer able to respond to a cancer treatment. The downstream of this is that we could end up with progression of the disease and need to look at alternative therapies that may be beneficial for the patient. This is unfortunately a very common phenomenon. Drug resistance is a major cause of treatment failure and poor patient outcomes with treatments. Unfortunately, this is an issue we see that increases over time on treatment.” TS 2:29

“Genetics play a really big role in drug resistance. We know that drug resistance can be due to different things. It could be epigenetics. It could be the tumor microenvironment factors. But genetics often play a very big role in resistance pathways. It’s generally considered to be a critical contributor to resistance, particularly in the way of acquired variants to drug targets or amplifications of certain oncogenes that can lead cancers to have progression. A well-known genetic alteration is the BRCA1/BRCA2 variant that helps to make the cancer more efficient at fixing DNA damage. So we’re trying to get DNA damage with chemotherapy, and this particular variant helps at fixing that damage to allow the cancer to progress. So that is one genetic variant we see that plays a big role in a number of different cancers.” TS 4:51

“These pathways are not mutually exclusive. Oftentimes we have multiple resistance pathways involved. I think it’s important to understand some of those individually, but kind of thinking about this as we might be facing multiple resistance pathways. ... We can see resistance mechanisms that vary based on the type of treatment we use, for example, traditional cytotoxic chemotherapy. We may be more likely to see some resistance mechanisms that are working at DNA: repairing broken DNA or working on those efflux pumps that are being used to push chemotherapy out of cells. If we’re talking more about the targeted therapies such as tyrosine kinase inhibitors or monoclonal antibodies, we may be more likely to see resistance mechanisms that are what we discussed with that drug target alteration: changing the way that the target agents are able to bind to the tumor cells to activate or inactivate pathways so we may see some changes there.” TS 12:39

“One way to overcome this and to help to decrease the resistance from developing is using combination therapy: drugs that are targeting different pathways at once or potentially using combinations with things like chemotherapy in addition to immunotherapy. In this way, as we’re getting these different targets, we can hopefully decrease the mechanism of resistance that may be developing.” TS 14:48

“Biomarker testing is an incredibly important part of our practice. In many situations now, we are getting upfront, comprehensive biomarker testing to identify whether the patient may have any of those intrinsic or primary resistance mechanisms that might make it so a patient is never going to respond to a particular type of treatment. And in that case, we can spare the patient from the potential toxicities of that treatment if we don’t think that there’s going to be benefit there. So I think that that has become a really important way that we can tailor patients for understanding what treatments are going to be more effective. And then after that, there’s usually additional biomarker testing that may be warranted at the time of progression in certain types of cancer. And that really helps us to understand that acquired resistance that might be developing.” TS 17:32

“Nurses are really helpful with filling in the gaps and bringing back patient concerns that might be shared with them. And these might be early signs of progression. Better understanding how our patients are feeling and what’s going on with them may help us to identify a patient that we need to do some additional testing for to understand whether there is drug resistance ongoing and potential progression of disease.” TS 21:52