In 2016, the research team led by Dr. Pavel Krejci published the following article:
Multikinase activity of fibroblast growth factor receptor (FGFR) inhibitors SU5402, PD173074, AZD1480, AZD4547 and BGJ398 compromises the use of small chemicals targeting FGFR catalytic activity for therapy of short-stature syndromes. Gudernova I, Vesela I Balek L, Buchtova M, Dosedelova H, Kunova M, Pivnicka J, Jelinkova I, Roubalova L, Kozubik A, Krejci P.
Turning this title into something comprehensible, the researchers said that the 5 agents/products (SU5402, PD173074, AZD1480, AZD4547 and BGJ398), known as TKIs (Tyrosine kinase inhibitors) showed great results in blocking FGFRs tyrosine kinases in dish cells (plates where the researchers put specific cells into a culture to be tested). The image below is an example of a cell culture plate.
There are 4 kinds of Fibroblast growth factor receptor (FGFRs): FGFR1, FGFR2, FGFR3 and FGFR4 and their actions (called signaling) are distinctive and involve diverse and multiple biological processes, including cell proliferation, survival, differentiation, migration, and apoptosis (means cell death) during embryonic development and adult tissue homeostasis. 5,7
FGFR 3 is the receptor where the mutation of achondroplasia is in chondrocytes and knowing that TKIs can block FGFR3, they can also block the other FGFRs. This means that TKIs target not just FGFR3 but all or almost all FGFRs.
FGFR3 is a major physiological negative regulator of bone growth, and therefore a safe and effective FGFR3 inhibitor would undoubtedly revolutionize the treatment of short-stature syndromes in general, possibly including many that are unrelated to FGFR3. 3
Credits: Khan Academy
So, in 2016, the team concluded that the 5 FGFR TKIs evaluated were poor candidates for therapy for achondroplasia, mainly because TKIs exhibited significant off-target activity. What does this mean? TKIs lack specificity for FGFR3, attack the other FGFRs, and show cell toxicity which would compromise TKIs’ use for treatment of achondroplasia. 3
Although Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of certain forms of cancers, and these agents are generally well tolerated, clinical experience with them has highlighted their unexpected association with serious toxic effects on various organs such as the heart, lungs, liver, kidneys, thyroid, skin, blood coagulation, gastrointestinal tract and nervous system. This occurs because tyrosine kinases are widely distributed with specific functional roles in different organs. 2
Recently, in August 2017, the same team published:
ARQ 087 inhibits FGFR signaling and rescues aberrant cell proliferation and differentiation in experimental models of craniosynostoses and chondrodysplasias caused by activating mutations, in FGFR1, FGFR2, and FGFR3.
ARQ 087 is a tyrosine kinase inhibitors that was tested in cultured chondrocytes (dish cells), and the team observed that ARQ 087 efficiently rescued all major effects of pathological FGFR3 activation as inhibition of chondrocyte proliferation, loss of extracellular matrix and induction of premature senescence. This means that in the cultured chondrocytes with the achondroplasia mutation and with ARQ 087, chondrocytes could grow and multiply as they do in a typical growth plate. Unfortunately, ARQ 087 has an off-target action too and blocks FGFR1, FGFR2 and FGFR3.
The main conclusion of the study is the following:
“The off-target effects of ATP-competitive TKIs represent a major obstacle compromising their use in the clinic, despite the fact that even serious side-effects may be tolerated in cancer, where the main objective is patient survival. In contrast, the side effects might not be acceptable in ACH or craniosynostoses, where the main treatment objectives are to increase stature height and correct disproportionate cranial development, respectively.” 4
This research proves that TKIs are not an appropriate selection to treat achondroplasia.
Developing new studies for achondroplasia can be very demanding and time-consuming, but patients trust that researchers do the best they can to deliver results that, ultimately, can be converted in a treatment and reduce the complications originated by achondroplasia: limbs and trunk disproportionality, neurologic, respiratory issues, orthopedic complications, negative social image, among others issues that are concerns and raise problems throughout life.
Not every study will originate a new medicine, but most studies will help researchers decide which way to go and which not to.
Author Comment: The title and text of this post was amended after reconsideration of previous content.
- Shah DR, Shah RR, Morganroth J. Tyrosine kinase inhibitors: their on-target toxicities as potential indicators of efficacy.Drug Saf. 2013 Jun;36(6):413-26.
- Gudernova I, Vesela I, Balek L, Buchtova M, Dosedelova H, Kunova M, Pivnicka J, Jelinkova I, Roubalova L, Kozubik A, Krejci P. Multikinase activity of fibroblast growth factor receptor (FGFR) inhibitors SU5402, PD173074, AZD1480, AZD4547 and BGJ398 compromises the use of small chemicals targeting FGFR catalytic activity for therapy of short-stature syndromes.Hum Mol Genet. 2016 Jan 1;25(1):9-23.
- Balek L, Gudernova I, Vesela I, Hampl M, Oralova V, Bosakova MK, Varecha M, Nemec P, Hall T, Abbadessa G, Hatch N, Buchtova M, Krejci P. ARQ 087 inhibits FGFR signaling and rescues aberrant cell proliferation and differentiation in experimental models of craniosynostoses and chondrodysplasias caused by activating mutations in FGFR1, FGFR2, and FGFR3. Bone. 2017 Aug 18. pi: S8756-3282(17)30311-3.
- Kai Hung Tiong, Li Yen Mah, and Chee-Onn Leong. Functional roles of fibroblast growth factor receptors (FGFRs) signaling in human cancers. Apoptosis 2013; 18(12): 1447–1468
- Ornitz D, Itoh N. The Fibroblast Growth Factor signaling pathway. Wiley Interdiscip Rev Dev Biol. 2015 May; 4(3): 215–266.