1931MO - A HER3/DUSP6 loop determines sensitivity to HER2-targeted therapies in breast cancer

Background

The majority of HER2+ breast cancer patients develop resistance to HER2 inhibitors and there is a pressing need for more efficacious therapies. Phosphatases are druggable targets but their role in HER2 therapy resistance is poorly understood. Dual specificity phosphatase (DUSP) 1 & 6 have key roles in tumor cell growth and apoptosis and their blockade augments chemosensitivity in human neoplasms. Here, we investigated the contribution of DUSP1 & 6 to resistance to HER2 inhibitors in breast cancer.

Methods

Genome editing; cell viability; Western blotting; RNA-seq; synergy analysis; xenograft, intracranial inoculation.

Results

DUSPs inhibition by RNAi and CRISPR procedures reduced cell viability and increased sensitivity to HER2 inhibitors in drug resistant cells and DUSPs overexpression promoted drug resistance in senstive cells. In an acquired resistant model with long-term exposure to Lapatinib, DUSP6 was highly expressed in the early stages of drug treatment and combination of Lapatinib or Neratinib with BCI, a DUSP1 & 6 inhibitor, prevented development of resistant clones. The AKT inhibitor MK2206 in combination with HER2-directed therapies is in clinical trials for the resistant disease. We found that compared to MK2206, BCI in combination with Lapatinib induced apoptosis in resistant cells. While MK2206 increased the expression of HER2 & HER3, BCI alone or in combination with Lapatinib reduced both HER2 and HER3. Consistently, RNAi-mediated depletion of DUSP6 reduced HER2 & HER3, implying for DUSP6-mediated regulation of HER2 & HER3. Moreover, mice injected intracranially with DUSP6 knockout cells had longer survival, compared with CAS9. Microenvironmental-mediated resistance to HER2 inhibitors occurs by the HER3 ligand heregulin (HRG). We found that BCI, but not MK2206, abrogates HRG-induced rescue in sensitive cells. Ultimately, a BCI+Lapatinib combination therapy reduced tumor growth in a xenograft model of resistant cells.

Conclusions

DUSP1 & 6 promote both inherent & acquired resistance to HER2 inhibitors and their inhibition provides important advantages over AKT blockade. Further investigation of the expression of DUSP1 & 6 in followed-up patients is warranted to further validate their role in resistance to HER2 inhibitors.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Prof. Jukka Westermarck.

Funding

A K. Albin Johansson Cancer Researcher grant from the Finnish Cancer Institute.

Disclosure

All authors have declared no conflicts of interest.