Targeted Therapy’s Achilles Heel: When Selectivity is a Liability

By Michael D. Taylor, Ph.D.

Introduction:

When the “War on Cancer” was declared in 1971, the weapons available were blunt instruments – mainly surgery and early forms of chemotherapy – resulting in limited efficacy and lots of collateral damage to the patient. Now, nearly 50 years later, new therapeutic platforms have improved our ability to treat cancer, but the tumor remains a determined and creative foe. We’ve gone through three stages: first, using a scorched earth approach with chemotherapy; second, deploying smart bombs with targeted therapies; and third unleashing the immune system with immuno-oncology drugs.

Every cancer is different so we must learn how to match these different therapies, deployed singly or in combination, with each tumor type to maximize response. Yet even when we do so successfully, the cancer often responds with new defenses resulting in drug resistance.

 

At an impasse when resistance hits

Nobody in the cancer world is a stranger to the challenge of drug resistance. Resistance develops to non-selective chemotherapies, to molecularly targeted drugs and even to immunotherapies. The precision targeted therapies that serve as ‘smart bombs’ to thwart cancer progression were designed to target specific mechanisms that support tumor growth (e.g. bevacizumab) or protein mutations (e.g. imatinib) that result in the increased cell proliferation that drives the disease.   In the face of such therapeutic pressure, tumor cells often respond by co-opting new molecular pathways or developing new mutations that cause drug resistance. In these cases, patients, who may have enjoyed significant clinical benefit for a time to a targeted therapy, are then often left without treatment options as the cancer evades the drug’s effects and may become even more aggressive. This resistance phenomenon occurs across tumor types including solid tumors such as breast or lung cancer as well as hematologic cancers like CML, and the mechanism of resistance can take many forms.   No molecular target is impervious either as inhibitors of VEGF, ABL, EGFR, HER2, ALK, KIT, and many others become ineffective over time in many patients due to the development of new mutations in the target protein or via work-arounds by activating other signaling pathways.

The conventional wisdom of targeted therapy is that successful drugs will be highly selective for the target – “Silver Bullets” – designed to hit only the relevant targets and spare related cellular processes, thus limiting the collateral damage, or toxicity, to the patient. Ironically, it is often the drug’s selectivity that is the feature tumor cells exploit to escape by developing new mutations in the target protein or finding alternative pathways to compensate for the drug’s inhibitory action. Selectivity is the drug’s “Achilles Heel.” To date, our primary solution to drug resistance is to develop a succession of new therapies, so that patients can move to a new ‘smart bomb’ after the previous one lost its power due to resistance. But for many tumors, the pace of resistance is too great, and the cancer escapes each new therapy and grows stronger. For drug developers, it becomes a game of “whack-a-mole” trying to produce a new drug for each new mutation. And importantly, with each progression of the disease the tumor burden increases creating ever more tumor cells that may evolve new resistance mechanisms.

There are a broad range of cancers and targeted drugs that fit this profile where targeted therapies become resistant. These include EGFR, ROS1 and ALK inhibitors for lung cancer, ABL inhibitors for CML just for example. Some limited progress has been made with “second generation” inhibitors that can target the original mutation and the newly identified resistant mutation. EGFR inhibitors are a notable example, but these too become susceptible to the next mutation to appear. For these tumors, the ideal “targeted therapy” is not selective for a specific protein mutation but has the power to address the current driver mutation and to smother new potential resistance mutations before they emerge to extend the duration of disease control and keep the tumor burden as low as possible.

Let’s consider one interesting cancer, gastrointestinal stromal tumors (GIST), in which nearly all patients hit this impasse and new drug resistance mutations arise in substantial numbers in response to targeted therapy.

 

GIST Example

Gastrointestinal stromal tumors (GIST) was one of the early success stories for targeted cancer therapies. One of the very first such therapies, imatinib (Gleevec), has dramatically changed the landscape for this formerly intractable cancer and improved prognosis for many patients living with this cancer by targeting the mutations in KIT kinase, which causes disease in the great majority of GIST patients. But inhibiting those driver mutations did not produce long-term disease control in most patients. New mutations emerged producing resistance. Sunitinib (Sutent) was developed for those imatinib-resistant patients, but resistance to sunitinib emerged even more rapidly than to imatinib. And the story repeats with regorafenib (Stivarga) developed for sunitinib resistance. Although the three targeted therapies extended the lives of GIST patients for a few years, 90% of patients end up with uncontrolled disease as they exhaust their therapeutic options. The GIST tumors, and the KIT gene that drives them, are slowed but not beaten.

 

 

The Battle Continues

With the medical need for drug-resistant GIST remaining great despite three approved targeted therapies, drug developers continue to bring forward new treatments.

Blueprint Medicines is developing BLU-285, which continues the strategy of targeting a subset of mutations, primarily Exon 17 KIT mutations which are common in later-stage GIST and a PDGFRα mutation (D842V) that causes GIST in a small fraction of patients.

But clearly for GIST, targeted therapies, once perceived as a ‘smart bomb’, ultimately fail because they were specifically designed to address a single mutation, or subset of mutations, while cancer cells are known to constantly mutate in an effort to evade inhibition. As a result, targeted therapies do not provide the breadth of mutational inhibition necessary to overcome treatment resistance and outsmart these constantly morphing cancer cells.

GIST, in particular, demands a broader approach because these tumors are so facile in developing mutations.

 

A Different Approach

In order to overcome the perennial challenge of treatment resistance in cancers like GIST, one drug developer is evaluating a different approach.

Deciphera Pharmaceuticals, a clinical stage biopharmaceutical company, is developing a new anticancer treatment that is still targeted, but designed to act more like a multiple-warhead missile than a smartbomb – hitting multiple mutations in the target protein simultaneously. This broad activity has the potential to address the full spectrum of KIT and PDGFRα mutations known to be active in GIST, with the goal of transforming GIST treatment at all stages of this disease.  DCC-2618 has shown promising activity in heavily pretreated late-stage GIST patients in a Phase 1 study.

Deciphera is committed to providing novel broadly acting therapies like DCC-2618 to cancer patients as quickly as possible. The Company recently initiated a Phase 3 pivotal trial with this pan-KIT and PDGFRα kinase inhibitor in fourth-line GIST patients, who have no approved treatment option. If successful, this study is intended to serve as the basis for regulatory approval in this patient population providing an important new option.

 

Dr. Taylor is President and CEO of Deciphera Pharmaceuticals. Prior to joining Deciphera, Dr. Taylor held senior leadership positions at Ensemble Therapeutics, Pfizer Inc. and Warner-Lambert/Parke-Davis.

 

References:

  1. “Resistance is futile: overcoming resistance to targeted therapies in lung adenocarcinoma,” Neel, D.S. and Bivona, T.G., Precision Oncology, 2017, 1:3
  2. “Drug Resistance to targeted therapies: Déjà vu all over again,” Molecular Oncology, 2014 , 8:1067-1083.
  3. “Targeted Therapy for Cancer in the Genomic Era,” Cancer J., 2015, 21: 294-298
  4. “How Cancers Evolve Drug Resistance,” The Scientist, April 2017
  5. “A History of Cancer Chemotherapy,” DeVita, V.T. , Jr. and Chu, E., Cancer Res., 2008, 68: 8643-8653
  6. Gastrointestinal stromal tumors: what do we know now? Christopher L Corless. Modern Pathology (2014) 27, S1–S16
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