Ruxolitinib mediates clonal evolution of RAS pathway mutations in MPN

The JAK inhibitor ruxolitinib was associated with RAS-mutated clonal evolution in myeloproliferative neoplasms (MPN). Mutations could occur in both clones with or without an MPN driver mutation. The presence of RAS mutations was associated with worse clinical outcomes in ruxolitinib-treated patients.

“Genetic resistance to targeted therapies in cancer, and especially in haematological cancer, have been well characterised,” said Dr Nabih Maslah (Université Paris Cité, France). “The major mechanism of resistance that was revealed was point-mutation of the oncogenic target, but it was recently demonstrated that downstream activation of the target is another mechanism of resistance in FLT3-mutated acute myeloid leukaemia (AML) [1,2].” The current study investigated whether JAK inhibition with ruxolitinib promotes clonal evolution in MPN [3].

In a selection of patients with myelofibrosis and available molecular data of the St Louis cohort (n=73), ruxolitinib treatment was an independent factor of RAS pathway mutation acquisition (HR 9.8; 95% CI 1.2–78.9; P=0.031).

To answer the question whether ruxolitinib treatment initiates clonal selection of RAS-mutated cells, CD34-positive cells were cultivated from patients with primary MPN known to harbour RAS pathway mutations. After 10 days of treatment with ruxolitinib, in cells treated with the JAK inhibitor, there was an increase in RAS mutation variant allelic frequency (VAF) and this was associated with a decrease of the MPN driver mutation (JAK2, CALR, or MPL) VAF. This raised the issue of potential co-occurring RAS mutations and MPN driver mutations within the same clones. DNA single-cell sequencing subsequently showed that RAS mutations can be acquired in either a driver or a non-driver clone.

Furthermore, Dr Maslah showed data that ruxolitinib-treated MPN patients who harboured RAS pathway mutations had worse clinical outcomes than patients with unmutated MPN (decreased transformation-free survival: HR 6.7; 95% CI 19–23.2; P=0.003). In patients who did not receive ruxolitinib, this association was not observed. Approximately half of the ruxolitinib-treated patients transformed to AML or myelodysplastic syndrome (MDS), whereas only 1 out of 6 ruxolitinib-untreated patients transformed to AML or MDS [4,5].

These results were further investigated and corroborated in JAK-mutated cell lines and murine models. The authors suggest screening for RAS mutations before treatment with ruxolitinib to avoid this clonal evolution and subsequent negative clinical outcomes.

1. Quek L, et al. Nat Med. 2018;24(8):1167–1177.
2. McMahon CM, et al. Cancer Discov. 2019;9(8):1050–1063.
3. Maslah N, et al. JAK Inhibition Mediates Clonal Selection of RAS Pathway Mutations in Myeloproliferative Neoplasms. Abstract 326, ASH 64^th Annual Meeting, 10–13 December 2022, New Orleans, LA, USA.
4. Santos FPS, et al. Leukemia. 2020;34(3):799–810.
5. Coltro G, et al. Blood Adv. 2020;4(15):3677–3687.

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Posted on 20 February 202315 February 2024