- This study explored reasons for acquired resistance to the CDK4/6 inhibitor ribociclib in five women with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer
- Examination of paired biopsies (obtained before treatment and at the time of progression) showed that acquired loss of RB, PTEN or both were potential drivers of resistance to ribociclib in four of the cases
- Four of five pretreatment biopsies (for one, data were unavailable) showed the tumors harbored additional PI3K pathway alterations (in either PIK3CA or AKT1)
- Some patients progressing on CDK4/6 inhibitors who have loss of PTEN may have diminished response to PI3Ka inhibitors
Three different CDK4/6 inhibitors—palbociclib, ribociclib and abemaciclib—are approved by the FDA as standard therapy in combination with endocrine therapy for women with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer. However, as with other targeted therapies, patients typically acquire resistance.
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Having lead a phase I study of ribociclib plus letrozole in this setting, Dejan Juric, MD, of the Mass General Cancer Center, and colleagues explored reasons for acquired resistance to CDK4/6 inhibitors. Their report appears in Cancer Discovery.
Acquired Loss of RB and PTEN Expression
For five patients treated in the trial at Mass General, the researchers were able to collect biopsies before treatment and at tumor progression. Two patients had loss of RB at progression, one had loss of PTEN and one had loss of both.
PTEN Loss Induces Resistance to CDK4/6
RB loss had already been evaluated in preclinical studies, but the team wanted to determine whether PTEN loss is a genuine mechanism of resistance to CDK4/6 inhibitors. They used gene-editing approaches to develop PTEN-deficient ER-positive breast cancer cells and also studied a PTEN-deficient mouse model of breast cancer.
In the cells, increased AKT activation mediated resistance to CDK4/6 inhibitors, and selective AKT inhibitors restored sensitivity both in vitro and in vivo.
In the paired biopsies, loss of PTEN expression correlated with exclusion of p27 from the nucleus, leading to increased activation of CDK4 and CDK2. Four of five pretreatment biopsies (for one, data were unavailable) showed the tumors harbored additional PI3K pathway alterations (in PIK3CA or AKT1).
Implications for Treatment Sequencing
Some patients progressing on CDK4/6 inhibitors who have loss of PTEN may have diminished response to PI3Kα inhibitors. This is of concern because the PI3Kα inhibitor alpelisib is now approved as second-line treatment for PIK3CA-mutated ER-positive breast cancer.
In contrast, breast tumors with RB loss may derive benefit from PI3Kα inhibitors comparable to that of cancers not exposed to CDK4/6 inhibitors.
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