Targeting Aberrant Signaling in Myeloid Malignancies: Promise Versus Reality

Key points

What makes a good drug-target pairing?

TKIs have been successful in the treatment of CML for clearly identifiable reasons. First and foremost, the ABL kinase domain is highly amenable to drug targeting. Second, the pathways that are activated by BCR-ABL play an essential role in the pathophysiology of CML. Third, inhibition of ABL does not result in unacceptable toxicity. Several decades of work identifying, validating, and targeting oncogenic enzymes has taught us that, for a drug-target pairing to be truly successful, all 3 of

Drugging the undruggable

Not all cancer-associated activating mutations in signaling proteins are amenable to molecular targeting. A classic example is the RAS family of small GTPases. RAS GTPases are among the most frequently mutated genes in cancer, and more than 10% of AML cases harbor activating RAS mutations.²³ Despite years of research, efforts to directly inhibit RAS have, to date, been unsuccessful.²⁴ One challenge to targeting RAS is structural. Unlike the ATP-binding domains of tyrosine kinases, which are

Oncogene addiction versus disease acceleration

In 2014, 3 groups reported that a significant proportion of older individuals with normal blood counts harbor somatic mutations in their hematopoietic stem cell compartment in genes associated with hematologic malignancies.31, 32, 33 This subclinical clonal hematopoiesis, termed clonal hematopoiesis of indeterminate potential (CHIP), is associated with an increased risk of developing hematologic malignancies. Prior studies on the mutational hierarchy of AML found that mutations in several

On-target toxicity as a therapeutic liability

Dysregulated JAK2 activation is the most common molecular feature of BCR-ABL–negative MPN. More than 90% of PV cases and approximately 50% of ET and PMF cases harbor JAK2V617F mutations,¹¹ and most JAK2V617F-negative ET and PMF cases harbor mutations in either Calreticulin (CALR) or the thrombopoietin receptor (MPL),40, 41, 42 both of which act to aberrantly activate JAK2 signaling. JAK2 activation appears to play a central role in the pathogenesis of BCR-ABL–negative MPN, and the observation

Where do we go from here?

The example of TKIs for the treatment of CML provides an important proof-of-concept that therapeutic targeting of kinases can have profound clinical benefits, but numerous efforts to target other oncogenic kinases have been less successful. A pessimist might view these setbacks as evidence that BCR-ABL is a unique oncogenic kinase that is not representative of the role of kinase signaling in cancer. But as we have discussed here, there is mounting experimental and clinical evidence to suggest

Summary

Although the extraordinary success of targeting BCR-ABL in CML has not, until now, been recapitulated in other diseases, much has been learned from these failures that will inform future efforts to target kinase signaling. Advances in our understanding of how kinase signaling promotes cellular transformation, and the advent of novel treatment strategies, are reasons for renewed optimism that more effective targeting of signaling pathways is not only possible, but is likely to significantly