Why Genetic Testing Matters Before Using Targeted Small Molecule Therapies in Cancer Treatment

Lucas Rodrigues, DVM, MS, PhD
Head of Veterinary Research at FidoCure

Precision medicine has revolutionized human oncology by enabling treatments tailored to the unique genetic makeup of each tumor. Now, this same approach is being increasingly adopted in veterinary medicine, bringing a new level of sophistication to cancer care in dogs. Small molecule targeted therapies are at the forefront of this movement, offering the potential for more effective and individualized treatments. However, their success depends on a critical first step: identifying the genetic drivers behind each tumor. Without this information, the use of targeted therapies becomes a gamble, especially risky in aggressive cancers with diverse genetic profiles, where delays in effective treatment can have serious consequences.

Not All Targeted Therapies Are Equal

Some small molecule inhibitors, such as toceranib, have a broad spectrum of activity. Toceranib was initially developed to inhibit the c-KIT receptor tyrosine kinase, which is mutated in approximately 9–45% of canine mast cell tumors^1–3. These mutations include internal tandem duplications (ITDs) in the juxtamembrane domain (exon 11), leading to constitutive activation of the receptor without ligand binding, as well as activating mutations in the extracellular domains, particularly in exons 8 and 9³. Due to its ability to also inhibit other kinases, such as VEGFR, PDGFR, FLT-3, and RET⁴, toceranib is often used empirically, even when a KIT mutation has not been confirmed. This has led to its widespread use not only in mast cell tumors , but also in various other tumor types, with the goal of blocking angiogenic and proliferative pathways regardless of c-KIT mutation status^5–11.

However, not all small molecule inhibitors offer this level of flexibility. Many newer-generation targeted therapies are designed with greater specificity, inhibiting a single genetic alteration or signaling pathway. These drugs are only effective when the tumor harbors the specific molecular target. Using them without confirming the presence of the corresponding alteration risks treatment failure, delays more effective options, and may result in lost time, especially in aggressive cancers where timely intervention is critical.

The Spectrum of Genetic Diversity in Tumors

The relevance of genetic testing becomes even clearer when looking at the genetic landscape of different tumor types:

• Mast cell tumors and gastrointestinal stromal tumors (GIST) frequently harbor consistent, well-characterized driver mutations, such as activating mutations in KIT^12,13. In these cases, identifying the mutation can directly inform the use of therapies like toceranib or other kinase inhibitors.
• In contrast, tumors such as splenic hemangiosarcoma, oral melanoma, osteosarcoma and soft tissue sarcomas display a wide array of genetic alterations. Recent studies have identified more than four distinct genetic profiles within some of these tumors, each potentially responding differently to targeted therapies^14–19.

In these heterogeneous tumors, a one-size-fits-all approach using small molecule inhibitors is not only ineffective, it can be harmful. Without a clear understanding of the signaling pathways driving tumor growth, clinicians risk administering treatments that offer no therapeutic benefit, allowing the disease to progress unchecked. In dogs with splenic hemangiosarcoma, for instance, tumors with TP53 mutations demonstrated sensitivity to HDAC or mTOR inhibition, whereas those with PIK3CA mutations responded primarily to mTOR inhibition²⁰. Importantly, TP53 and PIK3CA mutations are found in approximately 40% and 17.4% of cases, respectively¹⁶.

Why Timing Matters

Aggressive tumors like splenic hemangiosarcoma and oral melanoma often progress rapidly. Initiating an ineffective therapy due to lack of genetic information can result in lost time, time that could have been used for more appropriate, evidence‑based treatment. For instance, in a study of canine splenic hemangiosarcoma, dogs treated with splenectomy plus chemotherapy and targeted therapy had a median survival time of 249 days for stage II disease, compared to just 141 days with chemotherapy alone (p = 0.009); similarly, for stage III dogs, median survival improved from 89 days to 139 days with the addition of targeted therapy (p = 0.0358)20. In many cases, a short delay to perform genetic testing is far outweighed by choosing a therapy that aligns with the tumor’s biology.

Precision Over Empiricism

Empirical use of small molecule therapies, based on tumor type or drug accessibility rather than genetic evidence, may sometimes be justified in emergencies or in tumors with low genetic variability, with highly recurrent driver mutations. However, as more targeted drugs enter the veterinary and human oncology landscapes, it becomes essential to shift toward precision medicine strategies that prioritize molecular profiling.

Genetic testing before initiating small molecule therapy is not just a best practice, it is often the key to unlocking effective treatment. By understanding the specific genetic alterations driving a tumor, clinicians can better match patients with therapies that will offer the most benefit, minimize unnecessary side effects, and improve outcomes. As cancer care continues to evolve, so must our approach to treatment, guided not just by tumor type, but by the unique genetic signature of each patient’s disease.

References

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