Chemical Reviews pubs.acs.

org/CR Review

cross the blood−brain barrier more efficiently, providing

opportunities to treat brain cancers or metastases.193
CDK4/6 inhibitors have been evaluated in clinical testing in
the treatment of advanced estrogen receptor positive (ER+)
breast cancer, representing around 70% of breast cancers in
women. The rationale for this approach is that estrogen is
mitogenic and drives cell proliferation, which is influenced by
an increase in levels of cyclin D1 and CDK4/6 activity.
Although such inhibitors have shown improved PFS, the
impact on the overall survival of patients is still to be fully
Figure 28. Exemplar cKIT inhibitors.
established. In addition, endocrine therapy, such as aromatase
inhibitors and the hormone therapy drug tamoxifen, are the
current standard of care for ER+ breast cancer patients. across other oncogenic targets, resistance may develop, and in
However, resistance to endocrine therapy commonly occurs, the case of cKIT this appears to be largely driven by additional
and in the majority of cases, there is a perturbed (but intact) acquired nonsynonymous mutations. These include V654A in
downstream retinoblastoma (Rb) axis which makes them exon 13 and the gatekeeper mutant T670I, with the latter
potential targets for CDK4/6 inhibitor combination therapies. mutation mirroring the resistance mechanism of BCR/ABL
In many countries a combination of a CDK4/6 inhibitor and toward imatinib. In addition, there were various inhibitor
endocrine therapy has evolved as a new standard of care for ER resistant mutations observed along the activation loop of the
+ breast cancer. kinase such as D816V.
In terms of resistance mechanisms to CDK4/6 inhibitors, a In response to the emerging mutations, additional
complete understanding is still to emerge and may depend on compounds have been identified, largely from reprofiling
whether the compounds are used as a monotherapy or in other kinase inhibitors, which again mirrors the history of
combination with endocrine therapy. As a monotherapy, BCR/ABL and other evolving stories of targeting mutation-
resistance has been reported due to an early adaptive change based resistance. Sunitinib and regorafenib were subsequently
impacting on durability of response, which is then followed by approved in 2006207 and 2013208 for second- and third-line use
a hard-wired resistance mechanism.194 One of the most in patients but have been reported with modest response rates
frequently observed changes in resistant cell is the loss of (<10%) and PFS of 4−5 months along with tolerability
mutation of the Rb protein,195,196 but upregulation of CDK6 challenges.209,210 Although these inhibitors have been reported
and cyclin E1 and E2, along with the activation of CDK2 have to have increased mutant coverage (binding modes shown in
also been reported. The activation of the MAPK pathway has Figure 29), this is often at the expense of broader kinase
also been implicated as a mechanism of resistance to such selectivity which limits their clinical utility and impact. Again,
agents.197 Further clinical trials are ongoing to target such a similarly to BCR/ABL, ponatinib has been reprofiled in this
resistance mechanism and include additional combinations setting with promising response rates as a second-line
with chemotherapy and mTOR or PI3K inhibitors to combat treatment (∼50%), but tolerability issues have been observed,
cross-talk in this pathway. In addition, drug research is likely due to the lack of kinase selectivity. Although ponatinib
targeting the selectivity inhibition of CDK2 as a potential inhibits the gatekeeper mutant T670I (Figure 29), V654A
method of overcoming the mechanism of resistance.198 appears as one possible treatment resistant mutant which may
CDK4/6 inhibitors have also been shown to enhance the be due to a steric clash.211
activity of anti-PD-1 agents in immune-oncology settings Further drug discovery efforts have targeted these resistance
providing an additional therapeutic option.199 mutations specifically, with the aim of increasing mutant
3.9. cKIT coverage but not at the cost of poor kinase selectivity.
Examples of more recent cKIT inhibitors which are now being
The type III receptor kinase cKIT activates downstream used in clinical trials include avapritinib (formerly BLU-285)
pathways and promotes cell survival and cell proliferation;200 and ripretinib (formerly DCC-2618), shown in Figure
when constitutively active it has been implicated as a driver of 30.212−214 These compounds are also being evaluated for
a number of cancers. Inhibitors of cKIT have demonstrated their use in comparative PDGFα mutations such as D842V.
measurable clinical benefits to patients, in particular for the Avapritinib is a type I inhibitor and has demonstrated
treatment of gastrointestinal stromal tumors (GISTs).201 promising response rates in early clinical trials in cKIT mutant
Approximately 85% of GISTs consist of activated (mutant) populations.215 In January 2020, the FDA approved avapritinib
forms of cKIT.202 The most common of these mutations is for the treatment of unresectable or metastatic gastrointestinal
V559D, located in the juxtamembrane region and the stromal tumor (GIST) harboring a platelet-derived growth
extracellular regions (exons 11 and 9 respectively) with factor receptor alpha (PDGFRA) exon 18 mutation, including
additional rarer mutations.203 There are also comparable D842V mutations. Ripretinib is a type II inhibitor and is also
mutations on the kinase PDGFRA, which are also targeted by showing promising response rates in heavily pretreated GIST
many cKIT inhibitors.204 Although a number of these were not patient populations.216 It was reported that a New Drug
originally discovered as cKIT inhibitors, a range of small Application (NDA) for ripretinib was submitted to the FDA in
molecule therapeutics is now available for the treatment of December 2019 for the treatment of patients with advanced
patients with cKIT mutations (Figure 28). The first-line GIST who have received a prior treatment of imatinib
therapy for patients is the BCR/ABL inhibitor imatinib, which (Gleevec), sunitinib (Sutent), and regorafenib (Stivarga).217
has demonstrated a PFS of between 1.6 and 2.3 years Although beyond the scope of this review to capture in
depending on the specific mutations present and was approved detail, there are additional clinical and preclinical compounds
by the FDA in 2001.205,206 However, as has been observed reported where discovery scientists have targeted further
Y https://dx.doi.org/10.1021/acs.chemrev.0c00383
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