Inhibitors of cyclin-dependent kinases CDK4 and CDK6 have been approved for treatment of hormone receptor–positive breast cancers. In contrast, triple-negative breast cancers (TNBCs) are resistant to CDK4/6 inhibition. Here, we demonstrate that a subset of TNBC critically requires CDK4/6 for proliferation, and yet, these TNBC are resistant to CDK4/6 inhibition due to sequestration of CDK4/6 inhibitors into tumor cell lysosomes. This sequestration is caused by enhanced lysosomal biogenesis and increased lysosomal numbers in TNBC cells. We developed new CDK4/6 inhibitor compounds that evade the lysosomal sequestration and are efficacious against resistant TNBC. We also show that coadministration of lysosomotropic or lysosome-destabilizing compounds (an antibiotic azithromycin, an antidepressant siramesine, an antimalaria compound chloroquine) renders resistant tumor cells sensitive to currently used CDK4/6 inhibitors. Lastly, coinhibition of CDK2 arrested proliferation of CDK4/6 inhibitor-resistant cells. These observations may extend the use of CDK4/6 inhibitors to TNBCs that are refractory to current anti-CDK4/6 therapies.

Highlights d Typhoid toxin causes DNA fragmentation in vivo not associated with inflammation d Infection with a genotoxin-producing bacterium induces senescence in vivo d The presence of senescent cells is associated with an antiinflammatory response d The anti-inflammatory effect is lost in mice with acute colitis

Highlights d The bacterial genotoxin CDT induces senescence and a SASP in activated CD4 T cells d ATM plays a key role in orchestrating the SASP but not in the induction of senescence d ATM orchestrates the SASP via downstream activation of the p38 MAPK d Infection with genotoxigenic bacteria increases the proportion of GL13 + T cells in vivo

Basal-like triple-negative breast cancers frequently express high levels of c-Myc. This oncoprotein signals to the core cell cycle machinery by impinging on cyclin E. High levels of E-type cyclins (E1 and E2) are often seen in human triple-negative breast tumors. In the current study, we examined the requirement for E-type cyclins in the c-Myc-driven mouse model of breast cancer (MMTV-c-Myc mice). To do so, we crossed cyclin E1-(E1 -/-) and E2-(E2 -/-) deficient mice with MMTV-c-Myc animals, and observed the resulting cyclin E1 -/-/MMTV-c-Myc and cyclin E2 -/-/MMTV-c-Myc females for breast cancer incidence. We found that mice lacking cyclins E1 or E2 developed breast cancers like their cyclin Ewild-type counterparts. In contrast, further reduction of the dosage of E-cyclins in cyclin E1 -/-E2 +/-/MMTV-c-Myc and cyclin E1 +/-E2 -/-/MMTV-c-Myc animals significantly decreased the incidence of mammary carcinomas, revealing arole for E-cyclins in tumor initiation. We also observed that depletion of Ecyclins in human triple-negative breast cancer cell lines halted cell cycle progression, indicating that E-cyclins are essential for tumor cell proliferation. In contrast, we found that the catalytic partner of E-cyclins, the cyclin-dependent kinase 2 (CDK2), is dispensable for the proliferation of these cells. These results indicate that E-cyclins, but not CDK2, play essential and rate-limiting roles in driving the proliferation of c-Myc overexpressing breast cancer cells.