LEUKEMIA: Combination of Erk1/2i and CDK4/6i in relapsed and refractory multiple myeloma

Despite advances in treatment, relapsed multiple myeloma (MM) remains incurable due to high relapse rates and the development of drug resistance

Despite advances in treatment, relapsed multiple myeloma (MM) remains incurable due to high relapse rates and the development of drug resistance

With recent studies demonstrating the high efficacy of Erk1/2 and CDK4/6 inhibitors in metastatic relapsed cancers, a research team hypothesized that simultaneous targeting of RAS/MAPK pathway molecules including Erk1/2 and cyclin-Ds could enhance MM cytotoxicity And to minimize side effects, they examined Erk1/2i, CDK4/6i, and Erk1/2i + CDK4/6i treatment with RAS MAPK using in vitro and in vivo preclinical models of MM .

Figure 1: Effects of Erk1/2i + CDK4/6i on MM cell lines and HD-PBMCs

Figure 1: Effects of Erk1/2i + CDK4/6i on MM cell lines and HD-PBMCs

Figure 2: Synergistic cytotoxicity of Erk1/2i + CDK4/6i on MM cells

Figure 2: Synergistic cytotoxicity of Erk1/2i + CDK4/6i on MM cells

Their studies showed strong synergistic (IC < 0.

Their studies showed strong synergistic (IC < 0.

Figure 3: Erk1/2i + CDK4/6i treatment triggers cell cycle arrest and induces apoptosis

Figure 3: Erk1/2i + CDK4/6i treatment triggers cell cycle arrest and induces apoptosis

Figure 4: Effects of ERK1/2i + CDK4/6i on gene and protein expression in MM cell lines

Figure 4: Effects of ERK1/2i + CDK4/6i on gene and protein expression in MM cell lines

Figure 5: Erk1/2i + CDK4/6i reduces tumor burden in the MM1.

Figure 5: Erk1/2i + CDK4/6i reduces tumor burden in the MM1.

Figure 6: Effects of Erk1/2i and CDK4/6i on primary MM cells (A 1, B1, B3)

Figure 6: Effects of Erk1/2i and CDK4/6i on primary MM cells (A 1, B1, B3)

Figure 7: Effect of ERK1/2i + CDK4/6i on primary MM cells co-cultured with or without BMSC-CM

Figure 7: Effect of ERK1/2i + CDK4/6i on primary MM cells co-cultured with or without BMSC-CM

Figure 8: Gene signature-based approach identifies targets associated with Erk1/2i + CDK4/6i therapy

Figure 8: Gene signature-based approach identifies targets associated with Erk1/2i + CDK4/6i therapy

Studies have shown that Erk1/2i + CDK4/6i treatment induces inhibition of key target molecules in Erk1/2 and CDK4/6 signaling, such as c-myc, p-RSK, p-S6, p-RB and E2F1, indicating that these On-target activity of inhibitors

Studies have shown that Erk1/2i + CDK4/6i treatment induces inhibition of key target molecules in Erk1/2 and CDK4/6 signaling, such as c-myc, p-RSK, p-S6, p-RB and E2F1, indicating that these On-target activity of inhibitors

Overall, this study provides a preclinical framework for a combined Erk1/2i + CDK4/6i clinical trial to target the Ras+CDK pathway to improve outcomes in MM patients

Original source:

Original source:

Adamia, S.

Adamia, S.
, Bhatt, S.
, Wen, K.
  et al.
 Combination therapy targeting Erk1/2 and CDK4/6i in relapsed refractory multiple myeloma.
  Leukemia  (2022).
https://doi.
org/10.
1038/s41375- 021-01475-z Adamia, S.
, Bhatt, S.
, Wen, K.
  et al.
 Combination therapy targeting Erk1/2 and CDK4/6i in relapsed refractory multiple myeloma.
  Leukemia  (2022).
https://doi.
org /10.
1038/s41375-021-01475-z

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