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Ask the experts: the potential of tyrosine kinase inhibitors in oncology

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tyrosine kinase inhibitor

In this ‘Ask the Experts’ feature, we spoke to a panel of experts working throughout the field of oncology to gain an insight into their current perspectives on the challenges and benefits of tyrosine kinase inhibitors (TKI’s). We discuss the role that tyrosine kinases play in tumor biology, if there are factors that affect TKI selection for patients, what the side effects are and how our experts believe TKIs will develop over the next 5 years. Discover more about this topic from our experts: Justin Taylor (Sylvester Comprehensive Cancer Center University of Miami Miller School of Medicine; FL, USA), Skye Montoya (Sylvester Comprehensive Cancer Center University of Miami Miller School of Medicine) and Tejas Patil (University of Colorado School of Medicine; CO, USA). Meet the experts here.

 

What role do tyrosine kinases play in tumor biology?

Justin Taylor (JT): Tyrosine kinases – and signaling through kinases more generally – are well studied pathways that contribute to cancer biology. One of the reasons they are so fervently studied is that small molecule inhibitors to tyrosine kinases have been some of the most successful targeted therapies in cancer to date. Despite this, much of what we know about kinase signaling in cancer is limited to the dozens of kinases for which we have known drugs. Part of our research is studying some of the other kinases that have not received as much attention in the past.

Skye Montoya (SM): Tyrosine kinases in healthy cells are responsible for cell-to-cell communication and downstream signaling that helps to mediate cell proliferation and growth. In cancerous cells, these pathways are often overexpressed and manipulated for the benefit of the tumor.

Tejas Patil (TP): Multicellular organisms live in a complex environment where signaling pathways play a crucial role in the development and maintenance of life. Tyrosine kinases are important mediators of this signal transduction process, leading to cell proliferation, differentiation, migration, metabolism and programmed cell death. Tyrosine kinases are a family of enzymes, which catalyzes the phosphorylation of select tyrosine residues in target proteins, using ATP. This process is critical for normal cellular communication and growth. In cancer, these pathways are frequently altered. Typically, the level of cellular tyrosine kinase phosphorylation is tightly controlled. In cancer, constitutive activation of tyrosine kinases results in unregulated activation of many growth signaling pathways that are not constrained by normal homeostatic processes. 

What factors affect which TKI is selected for a specific patient?

JT: As mentioned before, TKIs are amongst the first targeted agents that were developed for cancer. Gleevac® (imatinib) is an inhibitor of a fusion kinase formed from BCR-ABL translocation in chronic myeloid leukemia (CML). Specific TKIs for CML like imatinib have been very successful at causing long-term remissions in that disease. Nowadays, patients with CML are expected to live as long as individuals of the same age without cancer. So, each patient might have a different TKI selected based on the disease and the specific molecular abnormality in their tumors.

SM: Each TKI has a specific target protein depending on the kind of cancer the patient is living with. Some protein targets acquire mutations and require more specific treatments. Within each new generation of TKIs, there are small adaptions made to not only target the normal (wildtype) protein, but also the most commonly occurring resistance mutations in that protein. Depending on the type of cancer, or the presence of mutations within the cancerous cells, doctors may choose to prescribe one TKI over another. Another factor that can often influence a patient’s treatment plan is the tolerability of side effects from each TKI.

TP: Patients with non-small cell lung cancer (NSCLC) should undergo broad-based molecular testing (ideally through a next-generation sequencing platform) to look for key oncogenes that have been identified in lung cancer. In 2022, driver mutations (oncogenes) that can be targeted using available TKIs include EGFR, ALK, ROS1, RET, NTRK, MET, HER2, BRAF V600E, and KRAS G12C. Depending on the underlying driver mutation, different TKIs may be available to patients. 

How do TKI’s affect cancer patients in the long-term?

JT: While TKIs have revolutionized cancer treatment, unlike some other cancer therapies, they are typically given continuously. Some exceptions to this include drugs like Rydapt® (midostaurin) which is given to patients with acute myeloid leukemia in combination with chemotherapy during induction and consolidation but not as continuous treatment. Long-term side effects can develop from TKIs that differ from the potential short-term side effects. Conversely, some short-term side effects may dissipate as they are adjusted to or treated with supportive agents. In some cases, studies have shown that patients with deep remissions may safely stop taking the drug after many years, and after consulting with their treating oncologist.

SM: Patients who are on TKIs long-term can face issues with their liver or kidney functions. Additionally – with some TKIs – extended treatment can increase the likelihood of resistance mutations generating in the cells, leading to disease progression.

TP: Since TKIs target a specific activating oncogene within cancer cells, they tend to have rapid and dramatic results. As these cancer cells are highly dependent on oncogene activation for survival and replication, blocking these pathways with TKIs results in an inability of cancer cells to exploit key signaling pathways for growth. As such, patients can have long-term cancer control. It is important to remember that these therapies do not generate cures but can result in prolonged duration of cancer control as long as patients continue to take the TKI. Eventually, cancers do evolve mechanisms of resistance to TKIs, and this remains an important challenge in cancer management. 

Since TKIs target a specific activating oncogene within cancer cells, they tend to have rapid and dramatic results.

What are the potential side effects of TKI’s and how does this affect cancer treatment?

JT: As opposed to chemotherapies, which share many of the same side effects, the diverse targets of TKIs can lead to a range of potential side effects. Many of the common side effects of TKIs are due to off-target inhibition of kinases that are not intended to be targeted in the tumors. These can be avoided by developing more selective agents. However, some on-target toxicities cannot be avoided. These side effects may lead to disruption of therapy or reduced dosing, which could potentially decrease the effectiveness of the treatments. It’s important for patients to let their doctors know about any side effects they are experiencing and to work with their doctor to address them.

SM: Different TKIs have a range of side effects. More selective TKIs can be more specific and have fewer side effects, however – as mentioned above – the continuous use of single target inhibitors often leads to the development of point mutations that cause resistance. Multi-targeting TKIs can help prevent or prolong the development of resistance or intolerance, but they do have a wide spectrum of side effects including nausea, vomiting, diarrhea, skin rash, hand-foot rash syndrome, myalgias, joint pain, fatigue and headaches for example. These side effects can often hinder the use or compliance of these inhibitors in a clinical setting.

TP: The side effects of TKIs are — in general — quite different from cytotoxic chemotherapy or immunotherapy. Given the selectivity of TKIs, the side effect profiles can vary dramatically depending on the underlying oncogene. For example, classic side effects from EGFR TKIs include a cutaneous rash, oral ulcers and diarrhea, largely driven by ‘off-target’ effects on wild-type EGFR receptors. In contrast, ALK TKIs as a class do not possess this side effect profile because they are targeting a different oncogene, therefore they have a different side effect profile. 

What blocks are preventing the widespread adoption of routing genomic/molecular testing in oncology?

JT: Currently, the biggest barrier is the cost of genomic testing and insurance coverage. In many cases, the patient may be asked to pay out-of-pocket for tests that can be quite expensive. As genetic testing becomes cheaper that may be less of an issue and more genetic testing is becoming part of the National Comprehensive Cancer Center (NCCN) guidelines, therefore more patients are becoming covered by insurance. The Sylvester Comprehensive Cancer Center is a National Cancer Institute (NCI)-designated Cancer Center and is paving the way for more broadly applied genomic and molecular testing.

Currently, the biggest barrier is the cost of genomic testing and insurance coverage.

SM: Several factors are currently preventing the widespread use of routine genomic/molecular testing. Some examples include doctor education or training, insurance coverage and the physical – patient specific – barriers, such as the location of the tumor or the pain/discomfort that can be associated with a biopsy.

TP: This is a challenging question with no single cause. Historically, there was a widespread belief that most patients with lung cancer are heavy smokers, and that the likelihood of finding actionable oncogenes amenable to TKIs was very low. Thankfully, most oncologists that I interact with, in the academic and community setting, have moved away from this mindset. I suspect that access to care and inequities in our health care system play a large role in why patients do not all get the appropriate biomarker testing needed. 

How could routine genomic/molecular testing expand the use of TKI’s as a treatment option for cancer?

JT: Currently, certain tumors with a relatively high percentage of targetable alterations are selected for molecular testing and there is nothing wrong with that. However, with more expansive testing we may be able to identify patients with molecular abnormalities that are not typical of that tumor type but still may respond to a TKI or other targeted treatment.

SM: The use of genomic profiling could be extremely advantageous in the treatment of cancers. By mapping the genetic profile and identifying specific genetic drivers associated with a particular cancer, you could better match a patient to the most efficacious treatment plan. This would allow patients to receive more selective TKIs, or a combination of multiple selective TKIs, that could target and eradicate the cancerous cells more quickly and efficiently.

TP: Routine testing would identify patients who may be candidates for targeted therapies and funnel these patients to receive TKIs earlier in their course of treatment.

The use of genomic profiling could be extremely advantageous in the treatment of cancers. By mapping the genetic profile and identifying specific genetic drivers associated with a particular cancer, you could better match a patient to the most efficacious treatment plan. 

 

In your opinion, how will tyrosine kinase inhibitors develop in the next 5 years?

JT: TKIs are still one of the largest class of drugs for use in cancer and I think that will continue to expand. As we further study some of the lesser studied kinases that I mentioned earlier, we may be able to develop new TKIs that can be applied to more tumor types. Some of our other research focuses on the development of resistance to TKIs and most of this work has been done with monotherapy TKI. I believe in the future we will be using more combination therapies, such as two TKIs, a TKI with another targeted agent or TKIs with immunotherapy or other types of novel therapies. The field is expanding immensely and growing fast. In the next 5 years, I hope we will have made tremendous progress in studying TKIs for use in the fight against cancer.

SM: In my opinion, I believe the TKIs that are currently available, will become more specific and will continue to better target, or even prevent, point mutations that currently cause resistance. Additionally, I believe that as our understanding of tumor biology develops, we will start to uncover new tyrosine kinases, or combinations of multiple kinases, that can be targeted.

TP: As I stated earlier, cancers will invariably evolve resistance to TKIs. A major challenge in cancer research is anticipating the evolutionary changes that occur within cancer cells. TKIs will be developed that deal with “on-target” resistances. These are mutations that typically evolve within the ATP-binding pocket and hinder the ability of the TKI to effectively bind to the target. The other interesting space will be the development of combination TKI studies where two TKIs are used at the same time to manage ‘off-target’ resistance. In this category of resistance, alternate signaling pathways get turned on and allow the cancer cell to survive in the presence of a TKI. An example of this is the activation of the MET pathway among patients with EGFR mutant NSCLC who are receiving a TKI called Tagrisso® (osimertinib). With activation of the MET pathway, a potentially rational combination to deal with this resistance mechanism would be to combine an EGFR inhibitor (osimertinib) with a MET inhibitor (Tabrecta® (capmatinib), Tepmetko® (tepotinib), or Xalkori® (crizotinib)). I anticipate many clinical trials using this combination approach in the coming years.

Meet the experts:

Tejas Patil: I am a medical oncologist practicing at the University of Colorado Cancer Center (CO, USA) with an interest in identifying novel biomarkers in thoracic malignancies, and the development of targeted therapies for lung cancer. My research interests revolve around two general themes: the first is to optimize clinical outcomes for patients with lung cancer by using molecular methods to identify prognostic and predictive biomarkers that allow for greater and more personalized selection of anti-cancer therapies. The second is to understand adaptive mechanisms utilized by cancer cells that allow survival following targeted therapies and to develop novel approaches to overcome these resistance mechanisms. Within my clinical practice, I see many patients with lung cancer who have no prior history of smoking. These patients disproportionately have specific ‘driver oncogenes’, which are activating mutations that trigger downstream signaling pathways. This allows a cancer cell to grow without any negative feedback. These driver oncogenes are unique in that many of them are amenable to targeted therapies using oral medications called tyrosine kinase inhibitors (TKIs).

Justin Taylor: I am an Assistant Professor in the Department of Medicine and the division of Hematology/Oncology at the University of Miami and a Member of the Cancer Epigenetics Program at the Sylvester Comprehensive Cancer Center (FL, USA). As a practicing oncologist I treat patients with hematologic malignancies, including patients receiving TKIs. I also run an independent research laboratory studying novel kinase inhibitors and resistance to current kinase inhibitor therapy.

 

 

 

 

Skye Montoya: I am currently a PhD candidate in the cancer biology program at the University of Miami (FL, USA). I study mutational resistance mechanisms of multiple tyrosine kinase inhibitors (TKIs) in B-cell malignant pathways.

 

 

 

 

 

 

The opinions expressed in this interview are those of the author and do not necessarily reflect the views of Oncology Central or Future Science Group.