Finding “The Goldilocks Zone” for Kinase Inhibitors

In the world of cancer therapeutics, the regulation of cell activation and proliferation plays a critical role in reducing tumor burden. While cell regulation is by no means trivial, doing so without damaging healthy cells or creating a number of unwanted side effects is even more difficult. This is frequently the reason why the vast majority of anti-cancer agents fail before they even get tested on humans. Quite simply, slowing or eliminating the growth of cancer cells while sparing normal cell activity has forever been the holy grail of drug companies. 

This paradox is especially true for a specific class of cancer therapeutics called kinase inhibitors. Protein kinases have long been the focus of cancer drug developers given their critical role in cell signaling and proliferation. What better way to stop cancer than to arrest the cancer cell division process itself? However, this promise does not come without tradeoffs, and in this regard, the challenge in regulating kinases is that they are also critical to the function of normal cells.

The early era of kinase inhibitors witnessed both triumphs and setbacks. Numerous drugs exhibited remarkable effectiveness against a wide range of cancers, yet many also encountered challenges related to dose-dependent toxicity. Such drugs frequently fell short of achieving an optimal dosage due to limitations imposed by their toxicities. While all patients react differently to drug toxicities, even including common medications like aspirin, many kinase inhibitors simply failed to reach a manageable balance between efficacy and toxicity for a significant portion of the patient population. Over time, the entire field of kinase inhibitors developed a stigma for being prone to dose-dependent toxicity.

How do we regulate kinase activity to arrest cancer activity but not enough to affect healthy cells? With over 500 unique kinases in the human kinome, targeting the right kinase(s) for cancer treatment is akin to finding the right kinase in the kinome haystack. Herein lies the paradox of selectively regulating kinase activity for anti-cancer activity while avoiding unmanageable toxicity of normal tissues.

The good news is that scientific discovery marches on. Our understanding of the function and interaction of protein kinases has advanced significantly over the past several years. We have identified specific groups of kinases connected in signaling pathways that are tightly coupled to cancer activation and proliferation. We’ve also discovered how activated kinases trigger or arrest downstream activity. More importantly, we now understand why kinase therapies for cancer often work wonderfully initially but quickly develop adaptive resistances which then require higher drug doses and correspondingly higher toxicities.

As the human kinome map becomes more clearly defined and understood, it also becomes more actionable. Researchers and biochemical investigators are using this information to develop new – not just optimized – treatments for a variety of common cancers. Each attempt to leverage the potential of kinase activation or inhibition for anti-cancer activity is met with an equally motivated effort to address the dogma of dose-dependent toxicity. All are in search of “The Goldilocks Zone” for kinase inhibitors -- a therapy that provides demonstrably durable anti-tumor activity but avoids indiscriminate effects on normal cells. 

At the recent American Association for Cancer Research annual meeting, several presenters discussed the topic of KRAS mutation cancers and their associated kinase-targeted therapies which comprise up to 25% of all cancer types. It was frequently noted that nearly all single-target KRAS therapies suffer a significant decline in effectiveness within several months. In response to this ongoing paradoxical treatment resistance, researchers promoted the concept of inhibiting multiple kinases to maintain anti-cancer activity. Several proposed the inhibition of EGFR in combination with other kinases to overcome treatment resistance in KRAS cancers. This has long been the strategy of MEKanistic Therapeutics who is actively advancing a new class of molecule towards the clinic targeting both PI3K and EGFR. To date, this new molecule MTX-531 has demonstrated impressive preclinical activity and durability against a variety of cancers, all seemingly within the kinase “Goldilocks Zone.”

Recognizing creativity and determination as the hallmarks of humanity, we remain bullish on the scientific community to move beyond the limitations of the past, to overcome the challenges of drugging high-value targets while sparring normal tissues, and to open entirely new areas of cancer treatments for a wide variety of vulnerable patients. To do otherwise is simply unacceptable, especially when the need remains exceedingly high and the possibility of success appears within reach. 

Oncology | Precision medicine | Biotech | Targeted treatment | Kinase inhibitor